Symptomatic Carrier Research Articles

The role of X-chromosome inactivation in the manifestation of Rett syndrome

X-chromosome inactivation (XCI) is random in the majority of patients with classical Rett syndrome (RTT). Preferential inactivation of the X chromosome with the mutated MECP2 gene is found in mildly symptomatic or asymptomatic carrier females. These findings lead to a hypothesis that random XCI is causally involved in the pathogenesis of RTT in heterozygous females. It is the cluster of functionally defective nerve cells lacking fully functional MeCP2 generated by inactivation of normal MECP2 allele that causes the wide spectrum of RTT symptoms. Thus, RTT is a rare human disease manifestation which is triggered most probably by random XCI.

Frontal lobe dementia with abnormal cholesterol metabolism and heterozygous mutation in sterol 27‐hydroxylase gene (CYP27)

Of the primary dementing disorders that cause frontotemporal dementia, the best-known is Pick disease. We report on a 44-year-old woman with progressive frontal lobe dementia and spastic paraplegia. Examination revealed increased serum levels of cholestanol with abnormal cholesterol metabolism and a heterozygous mutation of the sterol 27-hydroxylase gene (CYP27). Biochemical findings were compatible with cerebrotendinous xanthomatosis (CTX); however, the clinical manifestations were very dissimilar. To our knowledge, a symptomatic carrier of this mutation among CTX patients has not been reported. We speculate that the present patient has a previously undescribed neurodegenerative disease related to abnormal cholesterol metabolism with this heterozygous mutation.

A successful pregnancy in a heterozygote for OTC deficiency treated with sodium phenylbutyrate

Ornithine transcarbamylase deficiency (OTC) is an X-linked disorder of urea synthesis that can cause hyperammonemic coma in the hemizygous men. Clinical manifestations in heterozygous women range from apparent normality to profound neurologic impairment. Cases of symptomatic carriers of OTC deficiency that have been successfully treated with drugs that activate new pathways of waste-nitrogen excretion have been described previously.1 However, to our knowledge, such long-term treatments have never been reported before in pregnant carriers of OTC deficiency, and nothing is known about their toxicity. We report a symptomatic carrier of OTC deficiency successfully treated with sodium phenylbutyrate during her pregnancy. A 27-year-old woman presented whose diagnosis of OTC deficiency was established using an enzyme …

Contribution of the glycoprotein Ia 807TT, methylene tetrahydrofolate reductase 677TT and prothrombin 20210GA genotypes to prothrombotic risk among factor V 1691GA (Leiden) carriers.

The cooperative effects of the GPIa 807TT, MTHFR 677TT and prothrombin 20210GA genotypes with the FV Leiden 1691GA (FVL) genotype were evaluated by comparing these genotype frequencies in 77 asymptomatic and 156 symptomatic heterozygous FVL carriers. The GPIa 807TT and MTHFR 677TT genotypes did not segregate within the symptomatic FVL carrier group and did not contribute to venous thrombotic risk in this patient cohort. There was no difference in the prothrombin 20210GA genotype frequency between asymptomatic FVL carriers and a random Caucasian control group; however, the prothrombin 20210GA genotype was nearly 5 times as prevalent (19/156 v 2/77; P < 0.02) in the symptomatic FVL carriers (odds ratio 5.21; 95% confidence interval 1.20-47.62), demonstrating that this important prothrombotic risk factor acts synergistically with FVL.

The X Chromosome and Recurrent Spontaneous Abortion: The Significance of Transmanifesting Carriers

If, as we have argued, a subset of female carriers of X-linked recessive lethal traits are genetically predisposed to spontaneous abortion, and if such carriers can reliably be ascertained via their skewed pattern X chromosome inactivation, it becomes possible to test the hypothesis that X-linked recessive lethal traits are a significant cause of RSA in the general population. Intrinsic to this argument are the assumptions that the trait is cell autonomous—that is, that it causes death or growth disadvantage to the cells with the mutant X active and that hemizygous males survive at least until the pregnancy is clinically observable through a positive bHCG test.To test this hypothesis, we have initiated a case-control study wherein we compare the frequency of highly skewed X chromosome inactivation in women with two or more unexplained spontaneous abortions to the frequency in female controls (Lanasa et al. 1998xSee all References1998). The women characterized with idiopathic RSA have undergone a complete evaluation to rule out any of the known causes of RSA described above (Stephenson 1996xFrequency of factors associated with habitual abortion in 197 couples. Stephenson, MD. Fertil Steril. 1996; 66: 24–29Abstract | Full Text PDF | PubMedSee all References1996). The controls are women from the same demographic region, with no known history of spontaneous abortion; furthermore, the cases and controls are age-distribution matched, so that the distribution of ages between the two groups is the same. Defining skewed X inactivation as preferential use of one X chromosome in ≥90% of peripheral leukocytes, we have found 7 (14.6%) of 48 to have skewed X inactivation. In contrast, only 1 (1.5%) of 68 control females exhibit this extent of nonrandom X inactivation. This finding is statistically significant, with P < .01 (Fisher's exact test, one-tailed).The frequency of nonrandom X inactivation is somewhat lower (1.5%) in our control group than has been reported previously. Other groups have estimated that the frequency of skewed inactivation (at the level of ≥90% silencing of one copy of the chromosome) as 3.2% (Gale et al. 1997xAcquired skewing of X-chromosome inactivation patterns in myeloid cells of the elderly suggests stochastic clonal loss with age. Gale, RE, Fielding, AK, Harrison, CN, and Linch, DC. Br J Haematol. 1997; 98: 512–519Crossref | PubMedSee all References1997) or 3.5% (Plenge et al. 1997xA promoter mutation in the XIST gene in two unrelated families with skewed X-chromosome inactivation. Plenge, RM, Hendrich, BD, Schwartz, C, Arena, JF, Naumova, A, Sapienza, C, Winter, RM et al. Nat Genet. 1997; 17: 353–356Crossref | PubMed | Scopus (189)See all References1997) in women of the same age in the population at large. Although case-control comparisons across studies may be perilous, it is interesting to note that, even when these higher estimates of skewing frequency are used for the control group, the frequency we observe in our group of RSA-affected women remains significant at the level of P < .05 (Fisher's exact test, one-tailed).Although the results presented here are clearly preliminary, it is interesting to speculate about the frequency of X-linked recessive lethal traits in the general population. Given a frequency of idiopathic RSA of 1 in 250 in the general population, and an affection rate of ∼1 in 7 in our case population, the population prevalence of X-linked lethals leading to RSA could be as high as 1 in 1,750. In fact, our ascertainment methodology will miss a large number of carriers, since, on average, a carrier would have to become pregnant five times to show two spontaneous abortions. Furthermore, there is great selective pressure against such traits. As X-linked recessive lethal traits can be passed on only to daughters, the carrier frequency should be halved in each generation. If 1 in 1,750, in fact, approximates the carrier frequency, then the new mutation rate must be 1 in 3,500. Since the highest-known single-gene–mutation rate is that of dystrophin at 1 in 10,000, a mutation rate of 1 in 3,500 indicates extensive genetic heterogeneity. This is consistent with the hypothesis that there are a significant number of vital genes on the X chromosome.RSA is a major women's health concern. As the application of molecular genetics to RSA advances, it will be possible to begin characterizing those genes that cause spontaneous abortion in the recessive state. The X chromosome inactivation assay affords a methodology by which female carriers of X-linked recessive lethal defects can be identified. Over time, then, by assembling familial pedigrees, the individual causative genes can be identified. The X-inactivation assay should become an important diagnostic tool in the clinical evaluation of women with RSA, as secondary skewed X inactivation will be the common denominator by which carriers of X-linked recessive lethal traits can be identified.

Deficiency of syntrophin, dystroglycan, and merosin in a female infant with a congenital muscular dystrophy phenotype lacking cysteine-rich and C-terminal domains of dystrophin

Primary deficiency of merosin is the cause of the classic form of congenital muscular dystrophy (CMD) accompanied by brain white matter abnormalities. We report a female infant with dystrophinopathy who was deficient in merosin in skeletal muscle. The patient had a phenotype of typical CMD and white matter abnormalities on brain MRI. Merosin was greatly reduced in the biopsied skeletal muscle. However, the expression of dystroglycan and syntrophin was also greatly reduced, and the immunoreactivity for the antibodies against the cysteine-rich/C-terminal domains of dystrophin was absent in the sarcolemma. Reverse transcriptase polymerase chain reaction analysis of the dystrophin gene revealed a complete lack of exons 71 through 74. In skeletal muscle, only the mutant gene was expressed. These results suggest that the patient is a symptomatic Duchenne muscular dystrophy carrier with skewed X-inactivation. This patient illustrates for the first time that a dystrophin abnormality can cause a secondary deficiency of merosin in dystrophinopathy. The reduction of merosin may account for the clinical phenotype of CMD and correlate with the white matter abnormalities in our patient.

Possible mechanism of anhidrosis in a symptomatic female carrier of Fabry's disease: an assessment by skin sympathetic nerve activity and sympathetic skin response

Fabry's disease, X-linked alpha-galactosidase deficiency, features a variety of autonomic abnormalities including anhidrosis. In this study, we measured the skin sympathetic nerve activity (SSNA), skin potential and sweat rate in a symptomatic female carrier to investigate the underlying pathophysiology of anhidrosis. The basal activity and responsiveness of SSNA were both fairly well preserved, although slightly reduced compared with the control levels. However, sweating was completely absent, despite the normal skin potential change in response to SSNA bursts. These results suggest that anhidrosis in Fabry's disease is a result of sweat gland dysfunction as well as abnormal SSNA.

Chorionic villus sampling in a patient who is an unusual carrier of hemophilia B

We describe a patient who is a carrier of hemophilia B, who was unusual in that she had symptoms and abnormal hematologic findings. She became pregnant and desired to have chorionic villus sampling for fetal sex determination. This was performed without complication. Her pregnancy continued, and she was delivered of a normal female infant with no complications for mother or infant. We believe this to be the first report of chorionic villus sampling in a symptomatic carrier of hemophilia B.

Myoblast transplantation between monozygotic twin girl carriers of Duchenne muscular dystrophy

Monozygotic twin girls, both carriers of Duchenne muscular dystrophy, only one a severe symptomatic carrier and the other asymptomatic due to opposite lyonization, were studied. Myoblast clones were obtained from a muscle biopsy of the asymptomatic carrier. PCR amplification showed that most (94%) of these clones produced normal dystrophin mRNA. Roughly 704 million myoblasts were produced from 119 clones. These myoblasts were transplanted into the extensor carpi radialis (ECR) and in the biceps of one arm of the manifesting carrier while the other arm acted as the control. The strength of the patient was evaluated in a series of pre- and post-tests and a biopsy was obtained about 1 yr after the transplantation. The myoblast injections produced a significant force gain (12%–31%) in wrist extension but no force gain for elbow flexion. Muscle biopsies on the injected and control muscles obtained 1 yr after the injections showed only a small increase in the number of dystrophin positive fibers and the presence of numerous small type II fibers. The small beneficial effect of this transplantation cannot be attributed to immune problems, the donor and the recipient being identical twins, but may be due to a low level of spontaneous muscle regeneration.

The prevention of acquired immune deficiency syndrome; Roles for aseptic technique procedure and implications for care providers

Educational efforts to prevent the spread of AIDS among health care providers require a combination of accurate information and the use of aseptic technique (a procedure for preventing disease transmission) in the practice environment. Acquired immune deficiency syndrome (AIDS), is a fatal disease caused by infection with the human immuno‐deficiency virus (HIV). Working in close proximity with AIDS patients in the practice environment makes the health care providers highly susceptible to the contraction of the disease. Routine adoption of aseptic procedures would reduce AIDS transmission from the symptomatic and asymptomatic carrier.

Characterisation of dystrophin in carriers of Duchenne muscular dystrophy

Dystrophin, the protein product of the Duchenne muscular dystrophy (DMD) gene, was studied in needle biopsy samples taken from the quadriceps muscle of 15 asymptomatic carriers of DMD (13 adults and 2 young girls) and one symptomatic adult carrier. Antibodies to N- and C-terminal regions of dystrophin were used for both Western blot analysis and immunocytochemistry and a monoclonal antibody to β-spectrin used to assess membrane integrity. All asymptomatic adult carriers showed some abnormality in dystrophin immunostaining but very few negative fibres were present. A clear mosaic of dystrophin positive and negative fibres was seen only in the adult symptomatic carrier and the two young girls. On a Western blot, all carriers studied had dystrophin of normal molecular weight, but most had reduced abundance. In adult carriers, the amount of dystrophin relative to normal controls varied, but it was unrelated to age, serum creatine kinase (CK) levels or to the degree of pathology. Carriers with normal CK showed abnormalities in dystrophin expression. The dystrophin immunoblotting profile of the 2 young girls was very similar to that of their mothers, but the mosaic pattern of immunostaining was not apparent in the older carriers. In conclusion, dystrophin immunostaining and Western blot analysis of biopsy samples from asymptomatic carriers is often abnormal and they may be useful additional aids for establishing carrier status, particularly in younger girls.

Dystrophin immunohistochemistry in a symptomatic carrier of becker muscular dystrophy

Immunohistochemical localization of dystrophin was studied in a symptomatic carrier of Becker muscular dystrophy (BMD). Muscle biopsy specimens from a female carrier showed findings compatible with slowly progressive muscular dystrophy by ordinary histochemical examinations. Immunohistochemical study, using an antiserum raised against a synthetic peptide fragment of dystrophin, demonstrated a mixture of staining patterns, including continuous but faint positive fibres, partially disrupted fibres and negative fibres. These findings were identical to those of patients with BMD and appear to differ from previous findings in female carriers of Duchenne muscular dystrophy. This report is the first immunohistochemical study of a symptomatic female proven by molecular genetic analysis to be a carrier of BMD.

Incidence of beta lactamase-producing Neisseria gonorrhoeae in a select population

THE RECENT ISOLATION of beta lactamaseproducing strains of Neisseria gonorrhoeae1-3 has produced well-founded concerns that these organisms might soon result in a serious public health problem in the United States. Soon after the appearance of the initial isolate’ at Travis Air Force Base, California, it became clear that military persons were bringing strains of this penicillin G-resistant organism to this country from Asia. Travis Air Force Base is a major debarkation point for military persons returning from Asian tours of duty. Therefore, these concerns prompted institution of a David Grant Medical Center (DGMC) gonococcal surveillance program to answer questions which included: Has the resistant organism become disseminated in our population? Are these strains more virulent than previously known strains? Are the symptomatic carrier rates similar to those observed with common strains of Nrisseria gonorrhoeae? Endocervical and, in some cases, rectal cultures were obtained randomly from women (women on active duty in the military or dependents of active-duty military persons) 15 through 35 years old and receiving care in the DGMC Obstetrics and Gynecology Clinics. In each case the alginate culture swabs were immediately applied into Thayer-Martin media* and placed within minutes in incubators. Appropriate cultures were also obtained from all persons seen in DGMC Clinics with signs and symptoms consistent with a diagnosis of gonorrhea or known contact with persons known to have gonorrhea. Swabs were plated on Thayer-Martin media and incubated at 37” C. in 5 per cent carbon dioxide media. Plates were read at 24 and 48 hours. All suspicious colonies were tested for Gram stain morphology,

C-Reactive Protein in Streptococcal Pharyngitis

This study was designed to explore whether the test for C-reactive protein (CRP) is useful in differentiating bona fide streptococcal infection from the symptomatic carrier at the time of the acute visit to the physician. Serial blood samples from 157 children with symptomatic pharyngitis and a positive culture for group A streptococci were analyzed for the presence or absence of CRP. These data were compared with the patients' antibody responses to two streptococcal extracellular antigens (antistreptolysin O and antistreptococcal deoxyribonuclease B). Seventy-eight percent of patients with serologically confirmed streptococcal pharyngitis had a positive CRP test at the initial visit. Conversely, if the CRP test was negative at the acute visit, only about 25% later showed an antibody response. This latter finding held regardless of the degree of positivity of the initial culture, the presence of exudate or adenitis, or the presence of a temperature greater than 38.3 C (101 F) or coryza. These data suggest that the CRP test may be helpful to the clinician, especially if this abnormal protein is absent at the time of the acute visit.

Hepatitis B and the HB-SAg carrier. An outbreak related to sexual contact.

Within six months, acute viral hepatitis, type B, developed in three individuals associated with a nursing home in Denver. This attack rate, 1.4 cases per 100 patients and employees, was apparently higher than the reported incidence of hepatitis B in Denver during the same period. Parenteral inoculations could not be implicated as the means of acquiring hepatitis B. However, two of the hepatitis patients had had sexual contact within six months before their illness with an employee who was an insulin-dependent diabetic and a symptomatic carrier of HB-Sg. In addition, anti-HB-S antibodies were detected in his homosexual roommate. Although the chronic carrier was a food-handler, a seroepidemiologic survey of the employee population showed no spread of HB-Sag by means of food or casual contact. Only 1 (4.6%) of 22 employees tested had anti-HB-S antibodies. These results suggest that household and, in particular, sexual contact with a symptomatic HB-SAg carrier may be an effective nonparenteral or inapparent parenteral mode of transmitting HB-SAg.

Hepatitis B and the HBsAg Carrier

Within six months, acute viral hepatitis, type B, developed in three individuals associated with a nursing home in Denver. This attack rate, 1.4 cases per 100 patients and employees, was apparently higher than the reported incidence of hepatitis B in Denver during the same period. Parenteral inoculations could not be implicated as the means of acquiring hepatitis B. However, two of the hepatitis patients had had sexual contact within six months before their illness with an employee who was an insulindependent diabetic and a symptomatic carrier of HB_sAg. In addition, anti-HB_santibodies were detected in his homosexual roommate. Although the chronic carrier was a food-handler, a seroepidemiologic survey of the employee population showed no spread of HB_sAg by means of food or casual contact. Only 1 (4.6%) of 22 employees tested had anti-HB_santibodies. These results suggest that household and, in particular, sexual contact with a symptomatic HB_sAg carrier may be an effective nonparenteral or inapparent parenteral mode of transmitting HB_sAg. (<i>JAMA</i>232:717-721, 1975)

Genetics of hereditary nephropathy with deafness (Alport's disease).

The inheritance of Alport's disease, hereditary nephropathy with deafness, has been re–examined using data from a large French–Canadian kindred and reports from the literature. Sibships in wliich a parent and grandparent were known to carry the gene were used to test for partial sex–linkage. A decrease, rather than the expected increase, in affected sons of affected males with an affected father makes this hypothesis untenable. No matter which grandparent was affected, mothers with the gene had equal numbers of affected and unaffected offspring of both sexes, as expected for autosomal dominant inheritance; fathers with the gene had a decrease from the expected proportion of affected sons and an increase in unaffected sons with no distortion of the sex ratio. The hypotheses of preferential segregation and of a sex–linked dominant modifier gene have likewise been discredited. The findings fit the expectation for autosomal dominant inheritance, with reduced penetrance in the sons of affected fathers; it is suggested that the unfavourable intrauterine milieu of the affected mother increases the penetrance of the gene in her sons to that in her daughters. This is supported by a lower frequency of affected offspring from asymptomatic than from symptomatic carrier mothers. The puzzle remains as to why there is a more serious disease, yet reduced penetrance in the males. Figures appropriate for genetic counselling are provided.