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Biomedical subjects

R N Schimke

Publications and source records attributed to R N Schimke.

At least 19 recordsLinked to original sources
PubMed1995

Genetic and biochemical normalization in female carriers of Duchenne muscular dystrophy: evidence for failure of dystrophin production in dystrophin-competent myonuclei.

We studied 19 symptomatic female carriers of the Duchenne muscular dystrophy (DMD) gene. Most of these dystrophinopathy patients had had an erroneous or ambiguous diagnosis prior to dystrophin immunofluorescence testing. We assessed clinical severity by a standardized protocol, measured X-chromosome inactivation patterns in blood and muscle DNA, and quantitated the dystrophin protein content of muscle. We found that patients could be separated into two groups: those showing equal numbers of normal and mutant dystrophin genes in peripheral blood DNA ("random" X-inactivation), and those showing preferential use of the mutant dystrophin gene ("skewed" X-inactivation). In the random X-inactivation carriers, the clinical phenotype ranged from asymptomatic to mild disability, the dystrophin content of muscle was > 60% of normal, and there were only minor histopathologic changes. In the skewed X-inactivation patients, clinical manifestations ranged from mild to severe, but the patients with mild disease were young (5 to 10 years old). The low levels of dystrophin (< 30% on average) and the severe symptoms of the older patients suggested a poor prognosis for those with skewed X-inactivation, and they all showed morphologic changes of dystrophy. The random inactivation patients showed evidence of biochemical "normalization," with higher dystrophin content in muscle than predicted by the number of normal dystrophin genes. Seventy-nine percent of skewed X-inactivation patients (11/14) showed genetic "normalization," with proportionally more dystrophin-positive nuclei in muscle than in blood. In 65% of the skewed X-inactivation patients, dystrophin was not produced by dystrophin-positive nuclei; an average of 20% of myofiber nuclei were genetically dystrophin-positive but did not produce stable dystrophin. Biochemical normalization seems to be the main mechanism for rescue of fibers from dystrophin deficiency in the random X-inactivation patients. In the skewed X-inactivation patients, genetic normalization is active, but production failure of dystrophin by dystrophin-normal nuclei may counteract any effect of biochemical normalization. In the skewed X-inactivation patients, the remodeling of the muscle through cycles of degeneration and regeneration led to threefold increase in the number of dystrophin-competent nuclei in muscle myofibers (3.3 +/- 4.6), while dystrophin content was on the average 1.5-fold less then expected (-1.54 +/- 3.38). Our results permit more accurate prognistic assessment of isolated female dystrophinopathy patients and provide important data with which to estimate the potential effect of gene delivery (gene therapy) in DMD.

Adult↗
PubMed1994

Detection of new paternal dystrophin gene mutations in isolated cases of dystrophinopathy in females.

Duchenne muscular dystrophy is one of the most common lethal monogenic disorders and is caused by dystrophin deficiency. The disease is transmitted as an X-linked recessive trait; however, recent biochemical and clinical studies have shown that many girls and women with a primary myopathy have an underlying dystrophinopathy, despite a negative family history for Duchenne dystrophy. These isolated female dystrophinopathy patients carried ambiguous diagnoses with presumed autosomal recessive inheritance (limb-girdle muscular dystrophy) prior to biochemical detection of dystrophin abnormalities in their muscle biopsy. It has been assumed that these female dystrophinopathy patients are heterozygous carriers who show preferential inactivation of the X chromosome harboring the normal dystrophin gene, although this has been shown for only a few X:autosome translocations and for two cases of discordant monozygotic twin female carriers. Here we study X-inactivation patterns of 13 female dystrophinopathy patients--10 isolated cases and 3 cases with a positive family history for Duchenne dystrophy in males. We show that all cases have skewed X-inactivation patterns in peripheral blood DNA. Of the nine isolated cases informative in our assay, eight showed inheritance of the dystrophin gene mutation from the paternal germ line. Only a single case showed maternal inheritance. The 10-fold higher incidence of paternal transmission of dystrophin gene mutations in these cases is at 30-fold variance with Bayesian predictions and gene mutation rates. Thus, our results suggest some mechanistic interaction between new dystrophin gene mutations, paternal inheritance, and skewed X inactivation. Our results provide both empirical risk data and a molecular diagnostic test method, which permit genetic counseling and prenatal diagnosis of this new category of patients.

Adolescent↗
PubMed1993

Congenital nonprogressive myopathy with Möbius and Robin sequence--the Carey-Fineman-Ziter syndrome: a confirmatory report.

Recently, we evaluated a 27-month-old boy with congenital generalized nonspecific myopathy, Möbius sequence, Robin sequence, and failure to thrive. We think the child has the same entity described by Carey, Fineman, and Ziter in 1982 [J Pediatr 101:353-364] and as such represents only the third example of this unusual syndrome. Review of the large number of conditions in which the Robin sequence occurs supports heterogeneity. Our case strengthens the Möbius-Robin association and further defines the Carey-Fineman-Ziter syndrome as a viable entity. It is most likely inherited as an autosomal recessive trait.

Abnormalities, Multiple↗
PubMed1992

Hyperthyroidism. The clinical spectrum.

Among the endocrine disorders, thyroid disease ranks second only to diabetes mellitus in prevalence. Hyperthyroidism accounts for a considerable portion of thyroid disease, occurring in both sexes and at virtually all ages. All forms of the condition are readily treatable, and the cost of treatment is not excessive, so accurate diagnosis has clear and satisfying rewards for both patient and physician. An awareness of the various causes of the disease and alertness to the often unusual ways that thyrotoxicosis can present are important elements of diagnosis. In addition, effective use of laboratory tests is essential.

Humans↗
PubMed1992

Case report: breast cancer in males--a genetic consideration.

For many years, it has been recognized that a portion of female breast cancer is inherited. More recently, the probable contribution of heredity to at least a subset of male breast cancer also has surfaced. This report, which describes affected brothers, a half sister, and the common paternal grandmother, provides further support for the role of genetic factors in male breast cancer. Also noteworthy was the presence of prostate carcinoma in the sibling with bilateral disease and in the unaffected father.

Adult↗
PubMed1991

Hypomandibular faciocranial dysostosis: report of an affected sib and follow-up.

Hypomandibular faciocranial dysostosis is a condition heretofore described only in a single case. We report the birth of an affected sister along with follow-up information on the initial surviving patient. While a primary error in neural crest development was postulated in this syndrome, subsequently discovered anatomical abnormalities suggest a more complex pathogenesis.

Abnormalities, Multiple↗
PubMed1990

Multiple endocrine neoplasia: how many syndromes?

The phrase multiple endocrine neoplasia (MEN) generally denotes an association of tumors so specific as to constitute a syndrome. Three well-recognized such syndromes exist. All are autosomal dominant traits and all have been tentatively mapped to specific chromosomes. Other purported endocrine tumor syndromes have been suggested either as new entities or as subtypes of the existing MEN syndromes. The evidence in favor of these contentions is examined critically. Only one "new" association, that of pheochromocytomas and islet cell tumors, seems reasonable, and even in this setting, some relatives have had manifestations of von Hippel-Lindau syndrome. There is no compelling reason why such conditions as von Hippel-Lindau syndrome, peripheral neurofibromatosis, McCune-Albright syndrome, and others should be reclassified as MEN syndromes, although awareness of their collective endocrine abnormalities is clinically important.

Adenoma, Islet Cell↗
PubMed1989

Ehlers-Danlos syndrome: a new oculo-scoliotic type with associated polyneuropathy?

Two siblings born to consanguineous Bedouin parents and grandparents are reported with the phenotypic features of Ehlers-Danlos Syndrome (EDS), type VI. In addition, the affected individuals have a polyneuropathy as confirmed by nerve conduction velocity, electromyographic and muscle biopsy studies. We propose that this clinical combination represents a distinct type of EDS.

Adolescent↗
PubMed1989

Unknown syndrome in sibs: microcephaly, seizures, mental retardation, congenital heart disease, and skeletal abnormalities.

We present two male sibs with a series of malformations including microcephaly, mental retardation, congenital heart disease, skeletal abnormalities, micropenis, and mild hypothyroidism. Both have had seizures. While the pattern of abnormalities is similar to that previously reported in this journal as an unknown syndrome, the facies is clearly distinct, the hypothyroidism is mild, micropenis is present, and there are additional minor skeletal abnormalities.

Bone and Bones↗
PubMed1987

Dominantly inherited renal adysplasia.

We are reporting on 7 families with both unilateral and bilateral renal agenesis (or severe dysplasia). This condition, termed hereditary renal adysplasia (HRA) [Buchta et al, 1973], is an autosomal dominant trait with incomplete penetrance and variable expression. Review of the literature on familial renal agenesis suggests that HRA is more common than previously supposed and may account for most recurrences of bilateral renal agenesis (BRA), even when the parents are normal. There are no consistent phenotypic differences between sporadic and familial renal agenesis. Associated non-urogenital anomalies, although more frequent in sporadic cases, have been reported in HRA. Use of several approaches, including the Weinberg Proband Method, segregation analysis, and empiric risk estimation, leads to the conclusion that autosomal dominant inheritance is the most likely pattern of transmission for most cases of renal agenesis. Penetrance is between 50% and 90%. Ultrasound study of the kidneys of parents, sibs, and other relatives is recommended in all families in which there is an individual with unilateral or bilateral renal agenesis. The empiric risk for recurrence of BRA in sibs has been estimated at 3.5% [Carter, et al, 1979] but in the offspring of affected or obligate heterozygotes for HRA, the empiric risk of bilateral severe renal adysplasia is 15-20%.

Genes, Dominant↗
PubMed1987

Nasopharyngeal carcinoma, aplastic anemia, and various malignancies in a family: possible role of Epstein-Barr virus.

We report on a family ascertained because of sibs affected with nasopharyngeal carcinoma. Other relatives had aplastic anemia or other malignancies and most were born of consanguineous parents. Epstein-Barr virus has been strongly implicated in the pathogenesis of nasopharyngeal carcinoma. It has also been suggested as a cause of aplastic anemia and other neoplasms. We postulate that this extensive German-Mennonite family has a heritable defect in the immune response to Epstein-Barr virus making its members at excessive risk for a number of different malignancies. This immunologic predisposition may be HLA associated and appears to be inherited as an autosomal recessive trait.

Adolescent↗
PubMed1987

Proximal 3p deletion in renal cell carcinoma cells from a patient with von Hippel-Lindau disease.

A case of proximal 3p deletion is reported in tumor cells from a patient with renal cell carcinoma and von Hippel-Lindau disease. This is the first report of this deletion with renal cell carcinoma. With the previously detected translocations at the same breakpoint, this report confirms the 3p14 breakpoint as critical in this neoplasm. This strongly suggests that renal cell carcinoma results from a change in the genetic material in the proximal short arm of chromosome #3.

Angiomatosis↗
PubMed1986

Endocrine studies in a male patient with choriocarcinoma and gynecomastia.

Sex hormone profiles were studied in serum and tumor extracts of a man with pulmonary choriocarcinoma and gynecomastia. Although levels of serum estrogens were elevated as expected, serum androgen levels were uncharacteristically quite high. Tumor extract contained increased quantities of both androgens and estrogens when compared with surrounding normal lung tissue, but lacked the enzymes necessary for androgen biosynthesis while retaining aromatase activity. It is concluded that unlike the usual male patient with choriocarcinoma, the tumor-derived beta-human chorionic gonadotropin stimulated testicular androgen production. These androgens were in turn concentrated by the tumor and converted in part to estrogens. Furthermore, gynecomastia can occur even in the face of high serum androgen concentrations provided total estrogen levels are also disproportionately elevated.

Adult↗
PubMed1986

Androblastomas and thyroid disease in postmenopausal sisters.

Androblastomas are virilizing ovarian tumors found predominantly in premenopausal women. Reported are two postmenopausal sisters with androblastomas, the first such occurrence in the literature. An association has been proposed between the familial occurrence of these tumors and thyroid adenomas or nontoxic goiter. Of the two patients studied, one had a history of Graves disease and the other had thyroid cancer. The authors conclude that the associated thyroid pathology in the families described and in the studied patients is inconsistent and does not represent a unique multiple endocrine neoplasia syndrome.

Adenocarcinoma↗
PubMed1985

Primary hypogonadism and partial alopecia in three sibs with müllerian hypoplasia in the affected females.

We describe 3 sibs, two females and a male, with hypogonadism, defective Müllerian development in the sisters, and partial alopecia consisting of cranial hair only in the center of the scalp. One sister had absent gonads, the other had streak ovaries; both had markedly hypoplastic internal genitalia. Their brother had hormonal and histologic findings consistent with germinal cell aplasia. In view of the fact that the parents were consanguineous, autosomal recessive inheritance of the syndrome is likely.

Adolescent↗