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In mammals, X-chromosome dosage compensation is achieved by inactivating one of the two X chromosomes in females. In mice, X inactivation is initially imprinted, with inactivation of the paternal X (Xp) chromosome occurring during preimplantation development. One theory is that the Xp is preinactivated in female embryos, because of its previous silence during meiosis in the male germ line. The extent to which the Xp is active after fertilization and the exact time of onset of X-linked gene silencing have been the subject of debate. We performed a systematic, single-cell transcriptional analysis to examine the activity of the Xp chromosome for a panel of X-linked genes throughout early preimplantation development in the mouse. Rather than being preinactivated, we found the Xp to be fully active at the time of zygotic gene activation, with silencing beginning from the 4-cell stage onward. X-inactivation patterns were, however, surprisingly diverse between genes. Some loci showed early onset (4-8-cell stage) of X inactivation, and some showed extremely late onset (postblastocyst stage), whereas others were never fully inactivated. Thus, we show that silencing of some X-chromosomal regions occurs outside of the usual time window and that escape from X inactivation can be highly lineage specific. These results reveal that imprinted X inactivation in mice is far less concerted than previously thought and highlight the epigenetic diversity underlying the dosage compensation process during early mammalian development. dosage compensation | epigenetics | imprinting | mouse development | X inactivation

Mutations in the DAX-1 [dosage-sensitive sex reversal-adrenal hypoplasia congenita (AHC) critical region on the X chromosome; NROB1] gene cause X-linked AHC associated with hypogonadotropic hypogonadism. DAX-1 encodes an unusual orphan member of the nuclear hormone receptor superfamily, acting as a transcriptional repressor of genes involved in the steroidogenic pathway. All DAX-1 mutations found in AHC patients alter the protein C terminus, which shares similarity to the ligand binding domain of nuclear hormone receptors and bears transcriptional repressor activity. This property is invariably impaired in DAX-1 AHC mutants. Here we show that the localization of DAX-1 AHC mutant proteins is drastically shifted toward the cytoplasm, even if their nuclear localization signal, which resides in the N terminal of the protein, is intact. Cytoplasmic localization of DAX-1 AHC mutants correlates with an impairment in their transcriptional repression activity. These results reveal a critical role of an intact C terminus in determining DAX-1 subcellular localization and constitute an important example of a defect in human organogenesis caused by impaired nuclear localization of a transcription factor.

X chromosome inactivation is the silencing mechanism eutherian mammals use to equalize the expression of X-linked genes between males and females early in embryonic development. In the mouse, genetic control of inactivation requires elements within the X inactivation center (Xic) on the X chromosome that influence the choice of which X chromosome is to be inactivated in individual cells. It has long been posited that unidentified autosomal factors are essential to the process. We have used chemical mutagenesis in the mouse to identify specific factors involved in X inactivation and report two genetically distinct autosomal mutations with dominant effects on X chromosome choice early in embryogenesis., During early preimplantation development, female cells have two active X chromosomes. As these cells begin to differentiate, they undergo X chromosome inactivation, the epigenetic process that results in the stable [...]

The worldwide pattern of single nucleotide polymorphism (SNP) variation is of great interest to human geneticists, population geneticists, and evolutionists, but remains incompletely understood. We studied the pattern in noncoding regions, because they are less affected by natural selection than are coding regions. Thus, it can reflect better the history of human evolution and can serve as a baseline for understanding the maintenance of SNPs in human populations. We sequenced 50 noncoding DNA segments each ~500 bp long in 10 Africans, 10 Europeans, and 10 Asians. An analysis of the data suggests that the sampling scheme is adequate for our purpose. The average nucleotide diversity ([pi]) for the 50 segments is only 0.061% [+ or -] 0.010% among Asians and 0.064% [+ or -] 0.011% among Europeans but almost twice as high (0.115% [+ or -] 0.016%) among Africans. The African diversity estimate is even higher than that between Africans and Eurasians (0.096% [+ or -] 0.012%). From available data for noncoding autosomal regions (total length = 47,038 bp) and X-linked regions (47,421 bp), we estimated the [pi]-values for autosomal regions to be 0.105, 0.070, 0.069, and 0.097% for Africans, Asians, Europeans, and between Africans and Eurasians, and the corresponding values for X-linked regions to be 0.088, 0.042, 0.053, and 0.082%. Thus, Africans differ from one another slightly more than from Eurasians, and the genetic diversity in Eurasians is largely a subset of that in Africans, supporting the out of Africa model of human evolution. Clearly, one must specify the geographic origins of the individuals sampled when studying [pi] or SNP density.

Deleterious mutations in RS1 encoding retinoschisin are associated with X-linked juvenile retinoschisis (RS), a common form of macular degeneration in males. The disorder is characterized by a negative electroretinogram pattern and by a splitting of the inner retina. To gain further insight into the function of the retinoschisin protein and its role in the cellular pathology of RS, we have generated knockout mice deficient in Rs1h, the murine ortholog of the human RS1 gene. We show that pathologic changes in hemizygous Rs1[h.sup.-/Y] male mice are evenly distributed across the retina, apparently contrasting with the macula-dominated features in human. Similar functional anomalies in human and Rs1[h.sup.-/Y] mice, however, suggest that both conditions are a disease of the entire retina affecting the organization of the retinal cell layers as well as structural properties of the retinal synapse.

Mapping of a new Simpson-Golabi-Behmel syndrome (SGBS) locus to chromosome Xp22 has been carried out in a family with a severe form of the syndrome an X-linked overgrowth syndrome with visceral/skeletal abnormalities associated. Not all of those with SGBS have demonstrated disruptions of the glypican-3 gene (GPB3) locus. Alterations in this gene, located on Xq26, are implicated in etiology of the more mild forms of the disorder. A second SGBS locus is on Xp22. The mapping project used 25 simple tandem-repeat polymorphism markers all across the X chromosome.

A germline mosaicism in families with Lowe syndrome has been characterized, and seven novel mutations in the OCRL1 (ital) gene identified. The oculocerebrorenal syndrome of Low (OCRL) is X-linked and characterized by major abnormalities of kidneys, eyes, and the nervous system and associated with mutations in the OCRL1 gene. This gene has been studied in eight unrelated OCRL patients. Two nonsense mutations and three frameshift mutations brought on premature termination of the protein. Two microsatellite markers were found for the OCRL1 locus and a germline mosaicism was seen in one family. Genetic counseling implications exist.

A new gene, termed transducin beta-like 1 or TBL1, has been isolated that appears to be involved in X-linked late-onset sensironeural deafness associated with ocular albinism. TBL1 has 18 exons covering about 150 kb in the Xp22.3 region next to the ocular albinism gene (OA1). The new gene has characteristics that place it in the WD-40-repeat protein family.

The genomic structure and mutations of the gene PHKA2, which encodes the alpha subunit of phosphorylase kinase, have been studied. Mutations in the PHKA2 gene are associated with both subtypes of X-linked liver glycogenosis (XLG). Five new mutations associated with XLG I were found, along with one new mutation for XLG II and one associated with both forms of XLG. Differences in the kinds of disease-causing mutations may account for the biochemical differences between XLG I and II.

To address the genetic basis for an unusual pattern of skewing in a family segregating a mutation in the dystonia-deafness peptide (DDP) gene the locus responsible for the variable skewing to the proximal long arm of the X chromosome, a region with both the XIST and the DDP genes, was mapped. The female carriers in the family have incompletely penetrant and variable X inactivation patterns in peripheral blood leukocytes. It seems that the skewed X inactivation comes from selection against cells having the mutant DDP gene on the active X chromosome. Skewing, however, is apparently not as severe as that seen for many other harmful X-linked mutations. DDP is an example of an X-linked gene for which mutations cause partial cell selection and incompletely skewed X inactivation in peripheral blood leukocytes.

About 12-17% of the embryos obtained by mating mice carrying the In(X)1H or Paf mutations are of the 39,X (X0) genotype. Depending on the mutant mice used for mating, the monosomic X chromosome can be inherited from the paternal ([X.sup.P]) or the maternal ([X.sup.M]) parent. The [X.sub.P]0 embryos display developmental retardation at gastrulation and early organogenesis. [X.sup.P]0 embryos also display poor development of the ectoplacental cone, which is significantly smaller in size and contains fewer trophoblasts than XX siblings. In contrast, [X.sup.M]0 embryos develop normally and are indistinguishable from XX littermates. In both types of X0 embryos, an X-linked lacZ transgene is expressed in nearly all cells in both the embryonic and the extraembryonic tissues, suggesting that X inactivation does not occur when only one X is present. Of particular significance is the maintenance of an active [X.sup.P] chromosome in the extraembryonic tissues where normally the paternal X chromosome is preferentially inactivated in XX embryos. The differential impact of the inheritance of X chromosomes from different parents on the development of the X0 embryos raises the possibility that the [X.sup.P] is less capable than the [X.sup.M] in providing the appropriate dosage of X-linked activity that is necessary to support normal development of the embryo and the ectoplacental cone. Alternatively, the development of the [X.sup.P]0 embryo may be compromised by the lack of activity of one or several X-linked genes which are expressed only from the maternal X chromosome. Without the activity of these genes, embryonic development may be curtailed even though all other loci on the [X.sup.P] chromosome are actively transcribed.

The role of OCI-5/GPC3, a heparan sulfate proteoglycan that is bound to the cell surface through a glycosyl-phosphatidylinositol (GPI) anchor, in the onset of apoptosis in mesothelioma and breast cancer cells was investigated. Colony forming efficiency assays, transient expression and generation of a clone expressing OCI-5/GPC3 were performed to examine the role of the GPI anchor and the glycosaminoglycan chains in the apoptosis. Results showed that OCI-5/GPC3 can induce apoptosis in the mesothelioma and MCF-7 breast cancer cell lines and that this induction is cell line-specific.

Transmission of maternal alleles at loci going the length of the X chromosome have been analyzed in 47 normal, genetic disease-free families. A significant deviation from the expected Mendelian 1:1 ratio of grandmaternal:grandpaternal alleles was found in males at loci in Xp11.4-p21.1. The distortion in inheritance ratio was manifested as a strong bias in favor of the inheritance of the alleles of the maternal grandfather. No evidence for significant heterogeneity was found and it seems the major determinant involved in the generation of the non-Mendelian ratio is epigenetic.

Renpenning syndrome is a form of X-linked mental retardation affecting men in a Mennonite family in Canada. Molecular techniques indicate that the syndrome maps to Xp11.2-p11.4. The maximum LOD score was obtained for markers between DXS1039 and DXS1068. This region overlaps localizations of other X-linked mental retardation syndromes. Phenotypically, Renpenning syndrome most closely resembles Sutherland-Haan syndrome.

Mutations in Btk, a tyrosine kinase, have been found in 90%-95% of males with presumed X-linked agammaglobulinemia (XLA). Other genetic defects probably account for the remaining 5%-10% of patients. A study was conducted involving 101 families in which males were diagnosed with XLA. Of 40 families with more than one affected member, 38 had mutations in Btk, and of 61 families with sporadic disease, 56 had Btk mutations.

Breeding experiments and family studies were undertaken to prove the existence of a recessive type of ectodermal dysplasia linked to the X chromosome of dogs. The disease is similar to the ectodermal dysplasia in the Tabby mouse and the anhidrotic/hypohidrotic ectodermal dysplasia (HED) in humans. These results reveal that the canine ectodermal dysplasia can be used as a model to further understand the genetics of HED.

Turner's syndrome causes lack of sexual development and short stature in some females and is the result of all or part of one of the two female X chromosomes being absent. A study of 80 females with Turner's syndrome, 25 with a paternally-derived X chromosome and 55 with a maternally-derived X chromosome show that those with paternally-derived X chromosomes have greater cognitive function and better social skills than those with maternally-derived X chromosomes. It is concluded that the paternal copy of the X chromosome contains a genetic locus for social cognition.

The mutations in ribosomal S6 kinase (Rsk)-2 gene present on the X chromosome are responsible for the Coffin-Lowry syndrome (CLS). Rsk-2 is a growth factor regulated serine-threonine kinase. Screening of 76 patients of CLS, detected deletion, nonsense, missense and splice site mutations in the Rsk-2 gene. Ser 227 in Rsk-2 is involved in maximal enzyme activity through autophosphorylation of the enzyme. S6 kinase assay of mutated Rsk-2 protein gives negative result. These indicate that loss of Rsk-2 function cause defects in the MAPK/RSK signalling pathway and is responsible for CLS.

The skeleton of a middle-aged adult male, found in the Late Epigravettian necropolis of Arene Candide cave (Italy) and dated to the XII millennium B.C., exhibits abnormal changes, including bowing deformities, stunted growth, enthesopathies, and increased bone density. The pattern of the observed changes is less consistent with diagnoses of metaphyseal chondrodysplasias, hypophosphatasia, dietary rickets, or diffuse idiopathic skeletal hyperostosis (DISH) than with X-linked hypophosphatemic rickets, which is the most likely etiological factor. This diagnosis may explain other abnormalities (exceptional elongation of the skull and bilateral absence of the lesser trochanter) displayed by other individuals from the same site. KEY WORDS Paleopathology, Rickets, Upper Paleolithic

A point mutation discovered in the SH2 domain of the Bruton's tyrosine kinase (Btk) gene from a patient with atypical X-linked agammaglobulinemia indicates that this disorder is likely a result of subtle mutations in the genes responsible for the more typical disorder. Agammaglobulinemia is a sex-linked, inheritable genetic disorder that results in the absence of gamma globulin in the blood, increasing the risk of infection. Genetic defects in the X-chromosome at Xq22 and the cytoplasmic tyrosine kinase gene Btk have been associated with the typical form of the disease. A multitude of genetic mutations appear to be involved in X-linked agammaglobulinemia. The mutation of the SH2 domain of the Btk gene appears to be one of these many subtle mutations that lead to the atypical form of the disease.

Male sterility in the distal one-fourth X chromosome of Drosophila simulans is due to the substitution of Drosophila simulans factors by interacting genetic components. High and low resolution mapping identify an epistatic complex involved in the sterility of the male hybrid. The factors do not produce sterility individually, but only for specific introgression combinations. Multilocus weak allele associations create dissimilarity in the reproductive features of closely-related species.

Studies on male dogs reveal a mutation in the alpha 5(W) gene suggesting that Canine X-linked hereditary nephritis (HN) can function as an animal model for human X-linked HN. This provides an animal model for a mutated basement-membrane collagen gene. The mutation leads to a premature stop codon that does not express the alpha 5(IV) gene.

The XIST locus in tiny ring X chromosomes from eight females with chronic mental retardation and multiple congenital malformations was observed using PCR, Southern blot analysis and in situ hybridization. The locus exhibits heterogeneity. The XIST locus is absent in certain rings, while sequences homologous to probes for XIST are present in others. The severe phenotypes result from the incapacity of these rings to inactivate.

X-linked lymphoproliferative disease (XLP) was first described in 1975, and a registry of XLP patients is helping researchers search for the genetic cause and develop treatments. XLP is a genetic disorder which causes patients to develop life-threatening reactions to infection by the Epstein-Barr virus (EBV). All 281 patients identified by 1993 have been boys, and 77% of them have died. The cause of death has been infectious mononucleosis, an EBV infection, or its complications, including hypogammaglobulinemia and B-cell lymphoma. An EBV vaccine is not available to prevent infection, and many treatments have been tried with little success. Transplantation of bone marrow from an unaffected sibling may show promise. The immunodeficiency caused by XLP may indicate that the genetic defects involves T cells.

Genetic studies on the 14C area of the X chromosome of Drosophila melanogaster, to isolate inactivated alleles of no-on-transient A (NONA), were conducted. NONA is a nuclear protein present in puffs on polytene chromosomes of several cell types. Sequence data reveals that the protein is comprised of a pair of RNA binding motifs located in several single-strand nucleic acid binding proteins. The hypomorphic alleles of this gene also consist of regularly distributed nonA RNA and NONA protein embryos.

No evidence was found of a benefit from treatment with oleic and erucic acids in the diets of adrenomyeloneuropathy patients. Adrenomyeloneuropathy is a recessive disorder characterized by myelopathy, peripheral neuropathy and cerebral demyelination, which occurs with very-long-chain fatty acids. The synthesis of very-long-chain fatty acids is inhibited by the administration of oleic and erucic acids. Plasma very-long-chain fatty acid levels declined to nearly normal by the tenth week. Even so, none of the 14 men with adrenomyeloneuropathy improved over a mean follow-up of 33 months. There was functional deterioration in nine men, coincident in four with new cerebral lesions on magnetic resonance imaging.

A gene that may be involved in X-linked adrenoleukodystrophy (ALD) has been identified using positional cloning techniques. ALD is a degenerative neurological disease having diverse phenotypical manifestations which may involve numerous factors such as immune response and helper genes. ALD involves impaired beta-oxidation of very-long-chain fatty acids (VLCFA). The newly discovered gene is not directly involved in the oxidation of VLCFA, but it may be involved in the transport of VLCFA-CoA synthetase into the peroxisomal membrane or functionally associated with it in the membrane.

* Objective.--To determine the cause of absent sexual development in a 17-year-old girl with end-stage renal disease. Design.--Case study. Participant.--Seventeen-year-old girl with end-stage renal failure. interventions.--None. Measurements/Main Results.--The patient had phenotypically normal external female genitalia, mullerian duct hypoplasia, and no ovaries. Her serum gonadotropin levels were in the castrate range at baseline and after gonadotropin-releasing hormone stimulation. Her karyotype, in lymphocytes and cultured fibroblasts, was 46,XX. Analysis of genomic DNA, following polymerase chain reaction-amplication with oligonucleotide primers corresponding to the Y-encoded zinc finger protein ZFY and the testis-determining SRY gene, showed Y chromosome material in a male control but none in the patient. Conclusions.--The results suggest a diagnosis of Frasier syndrome, a disorder characterized by true gonadal dysgenesis and end-stage renal disease occurring in normal phenotypic girls. Although previously reported only in individuals with a 46,XY karyotype, our studies indicate that Frasier syndrome may also occur in 46,XX girls. Delayed puberty is not uncommon in renal failure. This case illustrates the importance of measuring gonadotropin levels in teenage girls with delayed puberty and renal failure, particularly if the origin of the renal disease is obscure. (AJDC. 1992;146:1218-1223)

DYT3, the gene locus of the X chromosome-linked dystonia-parkinsonism syndrome (XDP), has been additionally explored inside Xq13 by using four dinucleotide tandem repeat sequences form Xq13-derived yeast artifical chromosomes. Dystonia and parkinsonism are characteristic of XDP, which is a genetically homogeneous, severe movement disorder.

PCR was used to amplify two anosmia of a candidate gene for the X chromosome-linked version of the Kallmann syndrome on the genomic DNAs from 18 unrelated patients suffering from the syndrome. This candidate gene is the KAL gene carring the X chromosome-linked Kallmann syndrome, and so is connected with kidney organogenesis. The Kallmann syndrome symbolizes the link between hypogonadotropic hypogonadism and anosmia.

The non-isotopic in situ hybridisation (NISH) involves visualizing fluorescent DNA and RNA probes hybridised to single cells, tissues or chromosomes. Innovations using NISH and a yeast artificial chromosome probe were used to detect the hybridisation complex present in only one X chromosome in female carriers of X-linked disorders. These were shown in female relatives of patients with Hunter syndrome and Duchenne muscular dystrophy.

The putative gene involved in choroideremia was identified by chromosome walking experiments using a probe isolated from the X;13 breakpoint of a female with choroideremia. The isolated cDNA was similar to a previously described choroideremia gene candidate. Expression studies in 34 males with choroderemia showed no alterations in the DNA, but reduced or absent expression levels of the gene transcript. These results indicate that the isolated cDNA contains the choroideremia gene.

The gene deficiency involved in the development of liverglycogenosis was identified. Liver glycogenosis is attributed to a deficient phosphorylase kinase (Phk), whose genes have been mapped to the X chromosome. AcDNA library of liver and muscle was screened using cDNA clones of the muscle- type alpha-subunit of Phk. The results showed that the gene coding for the liver Phk is expressed by a different gene from that coding for muscle Phk. Thegene was mapped to the distal short arm of the human X chromosome, at Xp22.2- p22.1.

Fragile X syndrome is the most common form of inherited mental retardation. Unlike many gene mutations located on the X chromosome, fragile X syndrome is not inherited as a simple sex-linked trait. In contrast with other sex-linked traits, about 35 percent of the female carriers have some mental impairment, and at least 20 percent of the males carrying the gene appear normal. Currently, most diagnoses are made on the basis of cytogenetic analysis; microscopic examination reveals an abnormality in the Xq27.3 region of the long arm of the X chromosome. However, this diagnostic method is not completely satisfactory. Furthermore, cytogenetic analysis is most likely to fail to identify carriers, people who carry the gene but are unaffected by the syndrome. Therefore, cytogenetic analysis is of little benefit for genetic counselling of possible carriers. Using molecular genetics, a test has now been developed that is both more reliable and simpler to perform than cytogenetic analysis. Restriction nucleases, special enzymes that cleave the DNA into highly specific pieces of manageable size, were used by researchers to investigate the genetic status of 511 individuals from 63 affected families. In all cases, the molecular analysis was able to determine if the person was genetically normal, carried the full fragile-X mutation, or carried a so-called premutation. This premutation is apparently responsible for the unusual inheritance pattern of the fragile X syndrome. All 103 males and 31 of the 59 females with the full mutation were mentally retarded. However, among the patients with the premutation, the rate of mental retardation was similar to that of the population in general. The existence of a premutation in one generation apparently sets the stage for the development of the full mutation in the next. The DNA diagnosis appears to be more reliable than cytogenetic analysis. The relative simplicity of the test makes it possible to test all patients with unexplained mental retardation or learning impairment, not just retarded patients with a family history suggesting fragile X. (Consumer Summary produced by Reliance Medical Information, Inc.)

There are many causes of hereditary nephrolithiasis (kidney stones). One type of hereditary kidney disease was found in a large extended family descended from Irish immigrants, and the pattern of inheritance and the symptoms of the disease are described. Of 162 family members, 9 males suffered from X-linked recessive nephrolithiasis and abnormal renal (kidney) function. X-linked recessive diseases are passed on by females, and inherited only by males. As expected, half of the sons born to mothers who carried the gene developed the disease. The progression of the disease in the patients is described, and a pedigree analysis of six generations is analyzed. The abnormalities found in these family members are different from those of other forms of X-linked recessive nephrolithiasis. These differences include the mode of inheritance, the lack of cysts, absence of deafness and bone disease, and the presence of kidney stone formation. The cause of stone formation in these patients is unknown, and laboratory tests of hormone levels, and calcium and uric acid excretion did not identify those at risk. This is a distinctive form of inherited kidney disease, and better definition of the biochemical and genetic abnormalities will depend on isolation of the abnormal gene on the X chromosome. (Consumer Summary produced by Reliance Medical Information, Inc.)

X-linked hypophosphatemia is a genetic disorder characterized by a defects in the mechanism that reabsorbs phosphate back into the kidney tubule and the kidney enzyme 1-alpha-hydroxylase, which normally converts 25-hydroxycalciferol to 1,25-dihydroxycalciferol. The gene for this disorder is carried by the X chromosome, a thread-like structure in the cell nucleus that determines female sex characteristics. X-linked hypophosphatemia results in abnormally low blood levels of phosphate, growth delay and defects in bone shape and structure due to impaired bone formation. This genetic disorder is treated with phosphate supplements to restore blood phosphate levels. Specifically, 1,25-dihydroxyvitamin D3 is given to restore levels of 1,25 dihydroxycalciferol and diuretics are given to increase elimination of fluids and calcium and reabsorption of phosphate. Diuretics prevent or reduce the side effects of treatment with 1,25-dihydroxyvitamin D3, which include elevated blood and urine levels of calcium. Unlike other forms of hypophosphatemia, X-linked hypophosphatemia is not associated with muscle weakness. However, lower than normal levels of inorganic phosphate have been detected in the muscle cells of patients with X-linked hypophosphatemia. Recent studies using the Hyp mouse, the animal model for X-linked hypophosphatemia, suggest that a hormonal factor may be responsible for the development of this disorder. Advances in genetic studies of X-linked hypophosphatemia include the identification and localization of two genes, Hyp and Gy. Future areas of research in X-linked hypophosphatemia are presented. (Consumer Summary produced by Reliance Medical Information, Inc.)

Fragile X /fra(x)~ syndrome is a disorder that normally affects mentally retarded males and is transmitted genetically on the X chromosome by the mother. Fra(x) syndrome results in abnormalities in both behavior and appearance. Some researchers claim to have found an association between fra(x) and hyperactivity and aggressive behavior, although there have been few controlled studies to prove such a relationship. In a controlled investigation, 45 pairs of mentally retarded individuals (36 male and 9 female pairs) with ages ranging between 2 and 42 years, were studied. One person in each pair was previously diagnosed with fra(x). To assess autism (withdrawal) and aggressiveness, questionnaires were administered to parents. Attention deficit, hyperactivity, and aggressive symptoms were no more likely to be found in fra(x) individuals than in other mentally retarded individuals according to the data collected. Since age, sex, and IQ were controlled for, it is not likely that major confounding variables were missed. Therefore, it is concluded that mentally retarded individuals with fra(x) syndrome are no more likely to display aggressive, hyperactive, or attention deficit behaviors than mentally retarded individuals without fra(x) syndrome. (Consumer Summary produced by Reliance Medical Information, Inc.)

Patients treated for X-linked hypophosphatemia may also develop calcium deposits in their kidneys, which may lead to an accumulation of acid in the kidney and impaired kidney function. Researchers evaluated the frequency of calcium deposits and overall kidney function of 34 patients with X-linked hypophosphatemia. Nineteen of the 34 patients had calcium deposits. There did not seem to be an association between treatment with vitamin D or phosphate and the development of calcium deposits. However, there was an association between length of vitamin D treatment and the severity of damage caused by the calcium deposits. Most of the patients with calcium deposits in their kidneys (84%) also had hyperchloremic metabolic acidosis, or elevated levels of acid as well as chloride., Background. X-linked hypophosphatemia is characterized clinically by rickets and growth retardation. Therapy of this disorder with phosphate and vitamin D often produces nephrocalcinosis. The long-term effects of nephrocalcinosis on renal function in patients with X-linked hypophosphatemia are unknown. The purpose of this study was to evaluate the prevalence of glomerular and tubular disorders in patients with X-linked hypophosphatemia who developed nephrocalcinosis. Methods. The creatinine clearance and the prevalence of renal tubular acidosis were compared in 19 patients with X-linked hypophosphatemia and nephrocalcinosis with 15 patients with X-linked hypophosphatemia without nephrocalcinosis. Results. Sixteen of the 19 patients (84%) with nephrocalcinosis had a hyperchloremic metabolic acidosis compared with one of the 13 patients without nephrocalcinosis (P < .01). The serum bicarbonate of patients with nephrocalcinosis was 20.0 [+ or -] 0.7 as compared to 24.5 [+ or-] 0.6 mmol/L in patients without nephrocalcinosis (P < .01). The urinary anion gap was positive in all patients with acidosis (+ 62.1 [+ or -] 13.3 mmol/L). The creatinine clearance was 125 [+ or -] 6 mL/min/1.73 [m.sup.2] in patients with nephrocalcinosis and 124 [+ or -] 7 mL/min/1.73 [m.sup.2] in those without nephrocalcinosis. Conclusion. Therapy of X-linked hypophosphatemia is often associated with nephrocalcinosis. Nephrocalcinosis is associated with renal tubular acidosis in patients with X-linked hypophosphatemia. Pediatrics 1996;97:91-93; X-linked hypophosphatemia, nephrocalcinosis, renal tubular acidosis., ABBREVIATION. TMP/GFR, tubular maximum for the reabsorption of phosphate per glomerular filtration rate. X-linked hypophosphatemia is the most common inherited abnormality in renal phosphate transport.[1] It is inherited as an [...]

The fragile X chromosome is familial disorder characterized by mental retardation. The abnormality associated with this condition may be visualized directly under the microscope. However, the preparation of chromosomes for viewing is laborious and the microscopic examination of chromosomes requires some expertise. Even with expertise, the misdiagnosis rate for such cytogenetic analysis is about 5 percent. This error rate is significant, since fragile X syndrome is the single most common cause of inherited mental retardation. Researchers have now shown that it is possible to use the techniques of molecular biology to obtain a more reliable diagnosis. The fragile region on the X chromosome, which is located near the end of the long arm, is characterized by a repeated triplet, CCG (the DNA bases cytosine, cytosine, guanine). Apparently, the more this sequence is repeated, the more serious is the resulting fragile X syndrome. A combination of specific DNA probes and gel electrophoresis were used to evaluate this repeated genetic structure in a pregnant woman. The woman had one normal X chromosome, which revealed a repeated sequence about 1,000 bases in length. The other X chromosome had a repeated sequence of 1,200 bases, suggesting that the woman was a carrier of the fragile X syndrome. A sample from the chorionic villi revealed that the fetus was male. DNA analysis of the male fetus revealed a repeated sequence of 2,300 bases, strongly suggesting the presence of the full fragile X gene, which would mean the child would be mentally retarded. Previous research has shown that the fragile X gene in affected males is methylated to varying degrees; that is, the DNA is chemically modified by the presence of methyl groups. DNA analysis performed after the termination of this affected pregnancy confirmed that this was the case for many tissues of the fetus. However, the fragile X gene in the chorionic villi was not methylated, indicating that the methylation of DNA in a biopsy of chorionic villi is not satisfactory for the prenatal diagnosis of fragile X syndrome. The DNA analysis method appears to be appropriate not only for prenatal diagnosis of fragile X syndrome, but also for the identification of unaffected gene carriers as well. (Consumer Summary produced by Reliance Medical Information, Inc.)

Males with fragile X syndrome are mentally retarded, and have long, thin faces with prominent jaws and protuberant ears. These patients tend to have large testes and autistic characteristics. It is now appreciated that the fragile X syndrome is the most common inherited cause of mental retardation. The diagnosis of fragile X syndrome is generally made by chromosome analysis, which is not only laborious, but is also inaccurate about 5 percent of the time. Most often the error is a false negative. In the December 12, 1991 issue of The New England Journal of Medicine, two research groups report the efficacy of using DNA probes to diagnose the presence of the fragile X gene. This may prove to be one of the first genetic disorders in which DNA analysis becomes the primary means of diagnosis. The disease has a particularly unusual mode of inheritance. Unlike most X-linked diseases, in which males with the gene are invariably afflicted, about one-fifth of males carrying the fragile X gene are unaffected. Conversely, about half the women carrying the gene are affected to some degree, and 35 percent are mentally retarded. Another peculiar feature of the inheritance of this disorder is that there seem to be no cases in which the disorder occurs as a spontaneous mutation; all affected individuals are born to mothers carrying the gene. This fact is surprising; since affected males are not likely to reproduce, it was anticipated that new mutations must occur frequently. The apparent lack of new mutations may be due to an unusual sequence of events. The fragile X mutation apparently must be preceded by a 'premutation'. This is a smaller region of fragile DNA than is observed in the full fragile X syndrome. Males with the premutation may or may not be retarded, but males with the full mutation are invariably retarded. Traditional chromosome studies cannot reliably distinguish the extent of the affected DNA, and therefore can not account for the difference between males who are carriers of the gene and males who are actually affected by fragile X syndrome. Further studies will be necessary to determine the actual prevalence of the fragile X mutation in the population. These studies should also determine the frequency with which the smaller premutation increases in size to become the full fragile X mutation. (Consumer Summary produced by Reliance Medical Information, Inc.)