Efficacy of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)-cytosine and 9-(1,3-dihydroxy-2-propoxymethyl)-guanine in the treatment of intracerebral murine cytomegalovirus infections in immunocompetent and immunodeficient mice

Human X-linked dominant hypophosphatemic rickets (HPDR I) is characterized by hypophosphatemia, hyperphosphaturia, abnormal vitamin D metabolism, and rickets/osteomalacia. Two closely linked hypophosphatemic genes, hypophosphatemia (Hyp) and Gyro (Gy), are known on the mouse X chromosome. The Hyp phenotype is the equivalent of the human X-linked hypophosphatemia, while the human equivalent of the Gyro mouse has not been unambiguously identified. We observed an Italian four-generation pedigree with a new form of X-linked recessive hypophosphatemic rickets (XLRH). We demonstrated that HPDR I and XLRH are two different X-linked genes and that XLRH maps in the Xp11.2 region at 0% recombination fraction from the DXS1039 locus. We discuss this new finding in relation to the identification of the human equivalent of the Gyro mouse and to the recent mapping in Xp11.22 of another X-linked recessive renal disorder named Dent disease.     

A PHEX gene mutation is responsible for adult-onset vitamin D-resistant hypophosphatemic osteomalacia: evidence that the disorder is not a distinct entity from X-linked hypophosphatemic rickets

Previous investigators described a kindred with an X-linked dominant form of phosphate wasting in which affected children did not have radiographic evidence of rickets, whereas older individuals were progressively disabled by severe bowing. They proposed that this kindred suffered from a distinct disorder that they referred to as adult-onset vitamin D-resistant hypophosphatemic osteomalacia (AVDRR). We recently identified a gene, PHEX, that is responsible for the disorder X-linked hypophosphatemic rickets. To determine whether AVDRR is a distinct form of phosphate wasting, we searched for PHEX mutations in affected members of the original AVDRR kindred. We found that affected individuals have a missense mutation in PHEX exon 16 that results in an amino acid change from leucine to proline in residue 555. Clinical evaluation of individuals from this family indicates that some of these individuals display classic features of X-linked hypophosphatemic rickets, and we were unable to verify progressive bowing in adults. In light of the variability in the clinical spectrum of X-linked hypophosphatemic rickets and the presence of a PHEX mutation in affected members of this kindred, we conclude that there is only one form of X-linked dominant phosphate wasting.     

Proteinuria, hypertension and chronic renal failure in X-linked Kallmann's syndrome, a defined genetic cause of solitary functioning kidney

BACKGROUND: Anosmia and hypogonadotrophic hypogonadism are the classic features of X-linked Kallmann's syndrome, a disorder caused by mutations of KAL, a gene expressed during kidney and brain development. About a third of patients have a solitary functioning kidney, but little is known about their renal morbidity. METHODS: We studied seven patients aged 22-35 years with X-linked Kallmann's syndrome and a solitary functioning kidney. RESULTS: Two patients developed significant proteinuria associated with mild to moderate arterial hypertension in the second to third decades of life. In one, proteinuria and renal impairment preceded the appearance of hypertension, and the disorder progressed to chronic renal failure. The remaining five patients had normal plasma creatinine concentrations and no significant proteinuria although four had borderline systolic and/or diastolic hypertension. In two sets of patients from the same kindreds, there was a striking discordance for the occurrence of renal morbidity. CONCLUSIONS: All patients with X-linked Kallmann's syndrome should be screened for renal malformations, and those with solitary kidneys require life-long follow-up to detect hypertension, proteinuria and renal failure.     

A new Rett syndrome family consistent with X-linked inheritance expands the X chromosome exclusion map

Although familial recurrences of Rett syndrome (RTT) comprise only approximately 1% of the reported cases, it is these cases that hold the key for the understanding of the genetic basis of the disorder. Families in which RTT occurs in mother and daughter, aunt and niece, and half sisters are consistent with dominant inheritance and variable expressivity of the phenotype. Recurrence of RTT in sisters is likely due to germ-line mosaicism in one of the parents, rather than to recessive inheritance. The exclusive occurrence of classic RTT in females led to the hypothesis that it is X-linked and may be lethal in males. In an X-linked dominant disorder, unaffected obligate-carrier females would be expected to show nonrandom or skewed inactivation of the X chromosome bearing the mutant allele. We investigated the X chromosome inactivation (XCI) patterns in the female members of a newly identified family with recurrence of RTT in a maternal aunt and a niece. Skewing of XCI is present in the obligate carrier in this family, supporting the hypothesis that RTT is an X-linked disorder. However, evaluation of the XCI pattern in the mother of affected half sisters shows random XCI, suggesting germ-line mosaicism as the cause of repeated transmission in this family. To determine which regions of the X chromosome were inherited concordantly/discordantly by the probands, we genotyped the individuals in the aunt-niece family and two previously reported pairs of half sisters. These combined exclusion-mapping data allow us to exclude the RTT locus from the interval between DXS1053 in Xp22.2 and DXS1222 in Xq22.3. This represents an extension of the previous exclusion map.     

Anaesthetic management of an adult patient with X-linked adrenoleukodystrophy

PURPOSE: Adrenoleukodystrophy (ALD) is a rare genetic disorder. Findings include various central nervous system problems in addition to adrenal insufficiency. We present a case of an adult man with X-linked ALD undergoing surgery. CLINICAL FEATURES: A 40-yr-old man with X-linked ALD presented with an intertrochanteric femoral fracture. Past medical history included recurrent lung atelectasis, urinary incontinence, mental retardation, seizure disorder, and adrenal insufficiency. No sedative pre-medications were ordered, but perioperative steroid coverage with 100 mg hydrocortisone was initiated. In the operating room, the patient would not allow placement of all monitors. Therefore, 1 mg midazolam then 275 mg thiopentone followed immediately by 40 mg rocuronium were used to induce anesthesia with the application of cricoid pressure and the remaining monitors. Fentanyl 50 micrograms i.v. was given soon after induction, and anaesthesia was maintained with nitrous oxide and isoflurane. No further muscle relaxant or opioid was administered and anaesthesia was uneventful. The trachea was extubated with the patient awake and he was taken to the recovery area in stable condition. CONCLUSION: Patients with X-linked ALD are rarely seen in a clinical setting because the condition is so uncommon. Adrenal insufficiency, mental retardation, and osteoporosis are major considerations for these patients. In addition, these patients are at risk for reflux, seizures, and major post-operative complications.     

Arrested rearrangement of TCR V beta genes in thymocytes from children with X-linked severe combined immunodeficiency disease

Human X-linked severe combined immunodeficiency disease (SCID) is an immunodeficiency disorder in which T cell development is arrested in the thymic cortex. B lymphocytes in children with X-linked SCID seem to differentiate normally. X-linked SCID is associated with a mutation in the gene that encodes the IL-2R gamma-chain. Because TCR-beta gene recombination is a pivotal initial event in T lymphocyte ontogeny within the thymus, we hypothesized that a failure to express normal IL-2R gamma could lead to impaired TCR-beta gene recombination in early thymic development. PCR was used to determine the status of TCR-beta gene-segment rearrangements in thymic DNA that had been obtained from children with X-linked SCID. The initial step in TCR-beta gene rearrangement, that of D beta to J beta recombination, was readily detected in all thymus samples from children with X-linked SCID; in contrast, V beta to DJ beta gene rearrangements were undetectable in the same samples. Both D beta to J beta and V beta to DJ beta TCR genes were rearranged in the thymic tissues obtained from immunologically normal children. We conclude that TCR beta-chain gene rearrangement is arrested in children with X-linked SCID. Our results suggest a causative relationship between the failure of TCR beta-chain gene rearrangements to proceed beyond DJ beta rearrangements and the production of a nonfunctional IL-2R gamma-chain.     

Arterial ketone body ratio and its modification by PGE1 in elderly patients during gastrectomy

Breeding studies are reported of a previously undescribed hereditary retinal degeneration identified in the Siberian Husky breed of dog. This disorder clinically resembles the previously reported autosomal recessive canine hereditary retinal degenerations collectively termed progressive retinal atrophy (PRA). However, the pedigree of the propositus, a male Siberian Husky, exhibited an X-linked pattern of transmission. This dog was outcrossed to three phenotypically normal female laboratory Beagles and two of their F1 daughters were bred to a phenotypically normal male Beagle, producing affected males in the F2 generation. Subsequent inbreedings produced further affected males and affected females as well. X-linked transmission was established by exclusion of alternative modes of inheritance and, consequently, the disease has been termed X-linked progressive retinal atrophy (XLPRA). This is the first reported X-linked retinal degeneration in an animal. Because of the many similarities of PRA in dogs to retinitis pigmentosa (RP) in humans, this new disease may not only represent the first animal model of X-linked RP (XLRP) but may well be a true homolog of one of the XLRP loci (RP2, RP3, RP6). It is the first retinal degeneration in dogs that can be assigned to an identified canine chromosome, and the first for which linkage mapping offers a realistic approach to proceed by positional cloning towards identifying the responsible gene locus.     

Emery-Dreifuss muscular dystrophy

Emery-Dreifuss muscular dystrophy (EDMD) is an inherited muscular disorder characterized by the triad of progressive weakness in humero-peroneal muscles, early onset contractures and cardiomyopathy with conduction block that shows a high risk of sudden death. In 1994, the gene responsible for X-linked EDMD has been identified to Xq28 (designated as STA), that encodes a serine-rich protein of 254 amino acids, named emerin. In 1996, we discovered a nuclear membrane localization of emerin in the normal skeletal, cardiac and smooth muscles, but not in the tissues from patients with X-linked EDMD who had a nonsense mutation in the gene. In conclusion, molecular and genetic analyses of emerin are essential for accurate diagnosis of patients with EDMD.     

X-linked ocular albinism and sensorineural deafness: linkage to Xp22.3

X-linked ocular albinism with late-onset sensorineural deafness (OASD) is an autonomous disorder that poses significant clinical problems, causing affected individuals to be blind and deaf by early middle age. Classical X-linked ocular albinism (without deafness; OA1) has recently been linked to markers in the Xp22.2-Xp22.3 region of the human genome. In the present report, a large South African family with OASD was investigated at the molecular level and tight linkage was found to the DXS452 locus at Xp22.3 using 25 informative meioses, with a maximum lod score of 7.1 at a recombination fraction of 0.00. These findings suggest that OA1 and OASD are allelic variants or that they may be due to contiguous gene defects.     

Dental findings in an adult with Lowe's syndrome

This paper describes the dental findings and care of a Chinese adult affected with oculo-cerebro-renal syndrome--Lowe's syndrome--a rare, X-linked recessive disorder, whose clinical manifestations include cataracts, mental retardation, and renal tubular dysfunction. Approximately 150 cases have been reported in the last 45 years. Little has been reported in the dental literature. This patient is described with particular reference to the dental findings, which include gross periodontal disease with severe bone loss, impaction of teeth in the permanent dentition, taurodontism, and underdevelopment of the maxilla and mandible. Dental treatment was aimed at arresting the periodontal disease and preserving the remaining dentition.     

X-Linked chronic granulomatous disease: mutations in the CYBB gene encoding the gp91-phox component of respiratory-burst oxidase

Chronic granulomatous disease (CGD) is a hereditary disorder of host defense due to absent or decreased activity of phagocyte NADPH oxidase. The X-linked form of the disease derives from defects in the CYBB gene, which encodes the 91-kD glycoprotein component (termed "gp91-phox") of the oxidase. We have identified the mutations in the CYBB gene responsible for X-linked CGD in 131 consecutive independent kindreds. Screening by SSCP analysis identified mutations in 124 of the kindreds, and sequencing of all exons and intron boundary regions revealed the other seven mutations. We detected 103 different specific mutations; no single mutation appeared in more than seven independent kindreds. The types of mutations included large and small deletions (11%), frameshifts (24%), nonsense mutations (23%), missense mutations (23%), splice-region mutations (17%), and regulatory-region mutations (2%). The distribution of mutations within the CYBB gene exhibited great heterogeneity, with no apparent mutational hot spots. Evaluation of 87 available mothers revealed X-linked carrier status in all but 10. The heterogeneity of mutations and the lack of any predominant genotype indicate that the disease represents many different mutational events, without a founder effect, as is expected for a disorder with a previously lethal phenotype.     

Norrie-Warburg syndrome: two novel mutations in patients with classical clinical phenotype

Norrie-Warburg syndrome (NWS) is a rare X-linked disorder characterized by blindness, which is invariable, deafness and mental disturbances, which are present occasionally. We describe here two novel mutations, a missense mutation (C126S) and a 1-base pair insertion (insT466/T467), together with a recurrent mutation (M1V), found in patients presenting with the classical clinical phenotype of NWS. All three mutations are likely to result in prominent structural changes of the norrin protein.     

Adrenoleukodystrophy: unusual clinical and radiographic manifestation

Adrenoleukodystrophy is an X-linked recessive peroxisomal disorder, characterized by progressive neurologic deterioration due to cerebral white matter demyelination and adrenal insufficiency. Onset is usually in childhood between ages 5 and 10, and its course is fatal within approximately 5 years. Initial symptoms are behavioral, gait, and auditory disturbances and may be a diagnostic dilemma. Abnormally raised plasma very long chain fatty acids (VLCFA) are diagnostic; computed tomography and magnetic resonance imaging findings show symmetrical occipital white matter lesions which progress in a rostralcaudal direction.     

Molecular biological studies on patients with nephrogenic diabetes insipidus]

Nephrogenic diabetes insipidus is a rare, mostly X-linked recessive disorder characterised by renal tubular resistance to the antidiuretic effect of arginine vasopressin. The gene responsible for the X-linked nephrogenic diabetes insipidus, the G-protein-coupled vasopressin V2-receptor, has been localised on the Xq28 region. In this study four patients were investigated with molecular genetic methods. Diagnosis was based on clinical symptoms and lack of increase of urinary osmolality after administration of the arginine vasopressin, or the synthetic vasopressin analogue DDAVP. Three different mutations (C112R, N317K, W323S) were found in three patients, while no mutation was detected in the fourth patient. Since earlier histiocytosis X has been diagnosed in this patient, this patient has probably central diabetes insipidus. Although the main symptoms of the disease can be found in all patients, there are significant differences in the seriousness of the symptoms as well as in some other symptoms. The explanations might be the different mutations in the V2-receptor gene and the various other genetic and environmental factors; these findings provide further evidence that X-linked nephrogen diabetes insipidus results from defects in the V2-receptor gene.     

Early estrogen replacement therapy reverses the rapid loss of trabecular bone volume and prevents further deterioration of connectivity in the rat

OBJECTIVES: X-linked myotubular myopathy (MTM1) is a rare developmental disorder of skeletal muscle characterized by the presence of central nuclei in biopsy specimens from affected male subjects. Until recently, the disorder was usually fatal within the first year of life. This study was undertaken to determine the outcome in long-term survivors (>1 year of age) with MTM1. METHODS: Clinical data were obtained on 55 male subjects from 49 independent North American families for which a mutation was identified in the X-linked myotubularin gene by direct genomic sequencing. Medical records were reviewed and families were interviewed to ascertain features at birth, length of survival, developmental milestones, and medical complications. RESULTS: Seventy-four percent (26 of 35) of the affected male subjects over the age of 1 year are living (range, 1 to 27 years); 80% remain completely or partially ventilator-dependent. In the absence of significant hypoxia, cognitive development is normal, and the muscle disorder appears nonprogressive. Several patients have had other medical problems not previously reported to be associated with MTM1. These include pyloric stenosis (4 male subjects from 3 families), spherocytosis (2 patients), gallstones (4 patients), kidney stones or nephrocalcinosis (2 patients), a vitamin K responsive bleeding diathesis (2 patients), and height >/=90% for age (40% of the patients). Six patients have had biochemical evidence of liver dysfunction, and 2 patients died after significant liver hemorrhage. CONCLUSIONS: These data suggest that the prognosis for X-linked MTM may not be as poor as previously reported. However, at least some long-term survivors appear at risk for medical complications involving other organ systems, and patients should be carefully monitored for these potentially life-threatening complications. The pleiotropic symptoms demonstrated in these patients strongly suggest that the function of the MTM1 protein is not limited to developing muscle cells.     

XXY male with X-linked dominant chondrodysplasia punctata (Happle syndrome)

Happle syndrome is an X-linked dominant disorder with presumed lethality in hemizygous males; familial occurrence is rare. We describe a family with Happle syndrome affecting individuals in 3 generations. A man in this family is the first known male patient with Happle syndrome. He is severely affected; this may be due to his 47,XXY karyotype.     

Etiological factors in manic-depressive psychoses

Fifty consecutive patients with bipolar affective psychosis are reviewed, and the genetic and electroencephalographic findings set against extant hypotheses about inheritance of the disorder and the etiological homogeneity of the syndrome. Inheritance in this sample appears usually not to be X-linked. The syndrome seems etiologically heterogeneous in that some patients have an early onset and prominent genetic determinants, while in others without apparent hereditary predisposition, the illness start later and show electroencephalographic evidence of cerebral dysfunction.     

MR findings in oculocerebrorenal syndrome

Oculocerebrorenal syndrome is an X-linked recessive disorder characterized by congenital ocular abnormalities, mental retardation, renal disease, and metabolic bone disease. We report a case of oculocerebrorenal syndrome and, using T1-, proton density-, and T2-weighted imaging sequences, are able to characterize two distinct white matter abnormalities: one lesion is punctate and has signal characteristics that parallel that of cerebrospinal fluid; a second lesion, found in association with the first, consists of patchy white matter abnormalities that are hypointense on T1-weighted images but hyperintense on proton density- and T2-weighted images.