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Biomedical subjects

M G Butler

Publications and source records attributed to M G Butler.

At least 91 records · Page 5Linked to original sources
PubMed1995

Molecular genetic analysis of mentally retarded males with features of the fragile-X syndrome.

The fragile-X[fra(X)] or Martin-Bell syndrome is the most common familial cause of mental retardation and is characterized by the presence of an Xq27.3 chromosome fragile site. Unstable DNA sequences representing large increases in the number of CGG trinucleotide DNA base repeats of the FMR-1 gene are located at the fragile site and responsible for the fra(X) syndrome. In order to identify whether cytogenetically normal yet mentally retarded males without a known cause of their retardation had expansion of the CGG repeat segment of the FMR-I gene, molecular genetic studies using Southern hybridization were performed with two DNA probes (fxa241 and Ox1.9) following digestion of genomic DNA from each patient with restriction enzymes Pstl and EcoRl/Eagl, respectively. DNA studies were performed on 20 (12.3%) out of 162 (122 white and 40 black people) cytogenetically normal mentally retarded males without a known cause of their retardation, but with high anthropometric discriminant values and/or clinical checklist scores identified previously and consistent with the fra(X) syndrome. None of the 20 males showed expansion of the CGG repeat of the FMR-1 gene detectable with the two probes used in this study. While heterogeneous single base pair substitutions, or small deletions or insertions in the FMR-I gene could exist in our patients, aberrations in other X-linked mental retardation genes, not identified to date but whose gene product can produce a phenotype similar to fra(X), either independently or in conjunction with the recently identified FMR-I protein, should be considered and are under investigation. Our study supports the idea that major FMR-I gene expansion detectable with Southern hybridization is rare in cytogenetically normal mentally retarded males, including those with physical and behavioural features seen in the fra(X) syndrome.

Adolescent↗
PubMed1995

Meniscal ossicle: radiographic and MR imaging findings.

PURPOSE: To determine the magnetic resonance (MR) imaging appearance of meniscal ossicles and correlate that with the radiographic and clinical features. MATERIALS AND METHODS: Radiographs and MR images were studied retrospectively in six patients with meniscal ossicles; all patients had intermittent discomfort in the knee, and five patients had experienced knee trauma. Imaging findings were correlated with the clinical history. Four patients underwent arthroscopy. RESULTS: All patients had a visible ossicle on conventional radiographs initially interpreted as a loose joint body. MR imaging features included a corticated marrow-containing structure within the substance of the medial meniscus near the tibial attachment that appeared as a rounded focus of increased signal intensity on T1-weighted images that decreased in signal intensity on T2-weighted images. CONCLUSION: Meniscal ossicles have a characteristic MR appearance that may help distinguish them from loose bodies. They should be considered diagnostically when a circumscribed ossification is identified near the posterior horn of the medial meniscus on radiographs.

Adolescent↗
PubMed1995

Genetic anticipation and abnormal gender ratio at birth in familial primary pulmonary hypertension.

The genetic basis of familial primary pulmonary hypertension (FPPH) is unknown, but the clinical and pathologic features are the same as in sporadically occurring primary pulmonary hypertension (PPH). Because few families with this disease have been reported, the mode of inheritance and genetic features have not been clearly established. We previously reported a tendency for decreasing age of onset in subsequent generations of affected families. The purpose of this study was to examine the pattern of inheritance in a large number of families in an attempt to find clues to pathogenesis. From 24 families we studied 429 members, 124 of whom were known to carry the gene for disease. We constructed cumulative mortality curves for each gender of the 99 affected individuals. We analyzed gender ratios of progeny of affected members and carriers and compared age at death of affected members by generation. More females (160) than males (122) were born to persons carrying the gene, p < 0.01, suggesting selective wastage of male fetuses or an abnormal primary sex ratio. Genetic anticipation was confirmed; the age at death was 45.6 +/- 14.5 versus 36.3 +/- 12.6 versus 24.2 +/- 11 standard deviation (SD) years in successive generations, p < 0.05. Five cases of male-to-male transmission were observed, excluding X-linkage. Age at death was the same for males and females. More females had the gene (84 females, 40 males) and more females with the gene developed disease (72 of 84 females [86%] versus 27 of 40 males [68%]). The disease has highly variable penetrance among families.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Dosage and allelic restriction fragment studies and PCR analysis of the H-ras locus in giant cell tumor of bone.

Several studies have shown that giant cell tumor of bone frequently exhibits telomeric associations, commonly at chromosome 11p, which is also the location of the H-ras oncogene. In addition, rare H-ras alleles are more common among cancer patients than among healthy controls and point mutations of this oncogene have also been reported in several malignancies. These data led us to investigate gene dosage, restriction fragment-length size, and point mutations for H-ras in giant cell tumor of bone. Quantitative Southern blot analysis revealed no amplification of the H-ras oncogene in tumor DNA compared with DNA from peripheral blood in the same patient or from control subjects. In addition, no point mutations were detected in codons 12, 13, or 61 (mutations of these codons have been reported in other neoplasms) of the H-ras gene. No differences were noted in restriction fragment-length polymorphisms between tumor and peripheral blood in the same patient and no loss of heterozygosity was detected. In addition, there was no increased frequency of rare H-ras alleles (8% of alleles) in giant cell tumor patients compared to controls (21% of alleles) in our study. However, large allele sizes (> 8.5 kb) were significantly overrepresented in GCT patients compared with healthy controls. In our study, three of 12 alleles were found to be rare in the healthy controls but were common among GCT patients. Our data suggest that the H-ras oncogene is unlikely to be the site of a biologically significant primary lesion in GCT tumorigenesis.

Adult↗
PubMed1994

Antley-Bixler syndrome: report of a patient and review of literature.

We report a patient with Antley-Bixler syndrome and review 13 patients from the literature. The cardinal features of this condition include craniosynostosis, severe mid-face hypoplasia, proptosis, choanal atresia/stenosis, frontal bossing, dysplastic ears, depressed nasal bridge, radiohumeral synostosis, long-bone fractures and femoral bowing, urogenital abnormalities and a normal karyotype. Early death was identified in 54% of the reported cases, usually due to respiratory complications. The oldest patient at the time of follow up was 10 years of age. Intellectual performance has been variable (developmental testing of our patient at 30 months of age showed a range of developmental skills equivalent to 6 to 11 months of age). Chronic respiratory distress, especially if accompanied by periods of apnea, may be important in the causation of mental retardation. Some patients with the syndrome have normal intelligence, which suggests a normally developing brain, particularly if a craniectomy is performed to treat sutural synostosis and indicates that there may be secondary factors (e.g., apnea) playing a role in the mental retardation (as seen in our patient with a history of apnea) in patients with the Antley-Bixler syndrome. Since choanal atresia/stenosis which diminishes the airway passage is a cardinal feature of this syndrome, choanal stenting should be performed on those patients with this finding during infancy to decrease the airway obstruction. All patients followed beyond infancy were ambulatory, including our patient at 35 months of age, who will take steps with assistance. Although most cases are sporadic, there were reports of recurrence in siblings of both sexes in two families, suggesting an autosomal recessive mode of inheritance.

Abnormalities, Multiple↗
PubMed1993

Metacarpophalangeal pattern profile analysis in Brachmann-de Lange syndrome.

We analyzed the metacarpophalangeal pattern profile (MCPP) of 19 individuals with Brachmann-de Lange syndrome (BDLS) and calculated a mean syndrome profile. Fourteen of 19 individuals with BDLS had significant positive correlations which indicated clinical homogeneity. Discriminant analysis of individuals with BDLS compared with a sample of normal individuals produced a correct classification rate of 100% based on a function of 2 MCPP variables that may provide a useful tool for assisting in the diagnosis of BDLS. An average pattern variability index calculated for the BDLS patients was 1.9 indicating an abnormal hand pattern in this syndrome.

Adolescent↗
PubMed1993

Metacarpophalangeal pattern profile analysis in Williams syndrome.

Many patients with Williams syndrome (WS) are not diagnosed until they are old enough to demonstrate the characteristic personality and facial changes. A number of these changes are quite subtle and none of them is present in all affected individuals. The cause of WS remains obscure and consequently, there are no cytogenetic, biochemical, or molecular studies to help in the diagnosis of patients in whom the diagnosis is uncertain. We have generated a mean WS metacarpophalangeal pattern profile (MCPP) on 21 clinically diagnosed individuals with WS. This mean syndrome profile shows that WS hands are smaller than average age-matched control hands and that the distal phalanx of the thumb is disproportionately large with respect to the rest of the hand. A mathematical model, which effectively discriminates WS patients from unaffected control individuals, was developed using discriminant analysis of the MCPP data. Of the 21 WS patients classified by this method, only 2 were misclassified as "normal." Similarly, 2 of the 24 control individuals were misclassified as "WS," yielding an over-all successful classification rate of 91%.

Abnormalities, Multiple↗
PubMed1993

Telomere reduction in giant cell tumor of bone and with aging.

Giant cell tumor of bone is a benign, primary skeletal neoplasm that has an unpredictable pattern of biologic aggressiveness, and cytogenetically demonstrates genetic instability by exhibiting telomeric associations. Molecular analysis of telomeres from giant cell tumor of bone demonstrated reduction of telomere length (average loss of 500 base pairs) in eight individuals when compared with their leukocyte DNA. Those tumors which exhibited telomeric associations were found to have a greater reduction in telomere length than tumors not exhibiting them. For comparison, eleven cytogenetically healthy control individuals (7 females and 4 males, age range 2 weeks to 70 years) were included in this study. They demonstrated loss of telomere size (average 40 base pairs per year) with advancing age and the greatest rate of telomere reduction was identified in the young. Thus, the functional consequences of telomere shortening in a neoplastic cell may prove fundamental to sustaining the transformed phenotype in giant cell tumor of bone.

Adolescent↗
PubMed1993

Molecular analysis of transforming growth factor beta in giant cell tumor of bone.

Giant cell tumor of bone (GCT) is a primary bone neoplasm with unique cytogenetic findings including telomeric associations. Elevated expression of message RNA for transforming growth factor beta (TGF beta), but not transforming growth factor alpha (TGF alpha), has been reported in this tumor. Further investigation of GCT was undertaken to determine whether genetic loci for TGF beta in GCT patients with and without chromosome abnormalities are altered. Due to the reported TGF beta overexpression in GCT, qualitative and quantitative Southern blot analyses with TGF beta 1 and TGF beta 2 and an internal control probe (p3-21) were performed with tumor DNA and DNA from normal tissue on ten patients with GCT and control individuals. No obvious TGF beta 1 or TGF beta 2 gene alterations were detected. Normal copy numbers were calculated when comparing tumor and normal DNA from GCT patients as well as DNA from control individuals. Abnormal chromosome findings, including telomeric associations, marker chromosome, double minutes, chromosome fragments, ring chromosomes (possibly representing intra-chromosome telomeric associations), and polyploid cells were observed in seven of the ten patients with GCT. Chromosomes 11, 16, 19, 20, and 21 were most commonly observed in telomeric associations, with the terminus of the long arm of chromosome 19 being the most frequent. We conclude that there are no TGF beta 1 or TGF beta 2 gene alterations detected in GCT with the methodologies described, and that telomeric associations are a reproducible cytogenetic characteristic of this neoplasm.

Adult↗
PubMed1993

The extracellular matrix of reparative tissue in the vitreous: fibronectin production in proliferative diabetic retinopathy membranes.

In a preliminary investigation into the origins of the extracellular matrix glycoprotein fibronectin in proliferative diabetic retinopathy (PDR) membranes, four globes containing PDR membranes were subjected to in situ hybridisation and immunohistochemical studies. Fibronectin mRNA was found in PDR membrane cells in two of the four globes. The fibronectin-producing cells exhibited fibroblast-like or macrophage-like morphology. Occasional intraretinal macrophage-like cells which contained fibronectin mRNA were also observed in three of the eyes. Variable fibronectin immunoreactivity was observed in all the PDR membranes, while the fibronectin staining pattern in the underlying retina was similar to that reported for albumin in eyes with breakdown of the blood-retina barrier. The findings suggest that fibronectin in PDR membranes originates from both plasma-derived fibronectin and the membrane cells, and support the concept that extracellular matrix components play an important role in PDR membrane progression.

Aged↗
PubMed1993

Multiplex PCR of three dinucleotide repeats in the Prader-Willi/Angelman critical region (15q11-q13): molecular diagnosis and mechanism of uniparental disomy.

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are distinct mental retardation disorders caused by a deficiency of paternal (PWS) or maternal (AS) contributions for chromosome 15 by either deletion or uniparental disomy (UPD). To further study the molecular mechanisms involved in these disorders and to improve molecular diagnostic methods, we have isolated three dinucleotide repeat markers in the PWS/AS critical region. An Alu-CA PCR method was used to isolate CA-repeat markers directly from yeast artificial chromosome (YAC) clones identified by probes IR4-3R (D15S11), LS6-1 (D15S113), and GABAA receptor B3 (GABRB3). Three markers with 6-11 alleles and 73-83% heterozygosities were identified and analyzed by multiplex PCR. Gene-centromere mapping was performed on a panel of ovarian teratomas of known meiotic origin, and showed the most proximal marker, IR4-3R, to be 13 cM (95% confidence limits: 7-19 cM) from the centromere of chromosome 15. Molecular diagnostic studies were performed on 20 PWS and 9 AS patients. In 17 patients with deletions, the parental origin of deletion was determined. Ten PWS patients were shown to have maternal heterodisomy. Since these markers are only 13 cM from the centromere, heterodisomy indicates that maternal meiosis I nondisjunction is involved in the origin of UPD. In contrast, two paternal disomy cases of AS showed isodisomy for all markers tested along the length of chromosome 15. This suggests a paternal meiosis II nondisjunction event (without crossing over) or, more likely, monosomic conception (due to maternal nondisjunction) followed by chromosome duplication.(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗
PubMed1993

Genetic conditions among patients receiving genetic services in middle Tennessee.

We reviewed genetics charts of 2235 patients seen from 1985 to 1990 at Vanderbilt University Medical Center, Nashville, Tennessee, and summarized the 20 most common reasons for referral (occurring in 1138 of the patients) and the diagnoses or conditions among patients receiving genetic services in one of four clinical settings (prenatal counseling clinics, general genetics clinics, outreach genetics clinics, and ward consultations). The five most common reasons for referral were advanced maternal age (> or = 35 years) (203/1138, or 18% of patients), followed by dysmorphic features/multiple congenital anomalies (MCA) (185/1138; 16%), developmental delay/mental retardation (MR) (168/1138; 15%), Down's syndrome (103/1138; 9%), and abnormal maternal serum alpha-fetoprotein (MSAFP) (74/1138; 7%). The five most common diagnoses or conditions identified for all genetics patients were advanced maternal age (> or = 35 years) (195/906; 22%), developmental delay/MR (111/906; 12%), dysmorphic features/MCA (107/906; 12%), Down's syndrome (88/906; 10%), and multiple fetal losses (57/906; 6%). Of the 20 most common diagnoses or conditions categorized in 602 of the 906 patients, a multifactorial cause was observed in 25% of those patients; a chromosomal cause was observed in 26% of cases of Down's syndrome, accounting for 55% of the chromosomal disorders; a single gene disorder was observed in 17% of patients; an environmental cause was seen in 4%; and an unknown cause was noted in 28%. We hope this study will help physicians in middle Tennessee and surrounding areas by increasing their awareness of the types and frequencies of genetic diseases so that misdiagnoses and delayed referrals can be avoided.

Abnormalities, Multiple↗
PubMed1993

Clinical and cytogenetic survey of institutionalized mentally retarded patients with emphasis on the fragile-X syndrome.

A detailed clinical and cytogenetic survey for the fragile-X syndrome was undertaken on 201 institutionalized mentally retarded males with no previously recognized cause of retardation, and the causes of mental retardation were summarized from a total of 595 institutionalized male and female patients after the review of their medical records including clinical and cytogenetic data. Among the 201 males clinically and cytogenetically examined, five (2.5%) had abnormal chromosome findings with four (2%) having the fragile-X syndrome. Twelve of the males (6.0%) were diagnosed with a single gene disorder. In the present study, mental retardation was classified as possibly due to multifactorial causes when a genetic syndrome, chromosome abnormality or environmental insult was not identified, but mental retardation was present in one or more first and/or second degree relatives, but did not follow a recognizable inheritance pattern. Hence, mental retardation was recorded in other family members and may indicate possible multifactorial causes in 45 males (22.4%). An environmental insult was noted in 25 males (12.4%); unexplained birth defects in three males (1.5%); a specific condition or diagnosis identified, but cause unknown (e.g. Rubinstein-Taybi syndrome) in 10 males (5%); and no diagnosis made in the remaining 101 males (50.2%). Of all 595 patients (334 males and 261 females), including the 201 males who had undergone a detailed clinical and cytogenetic evaluation, 39 (6.6%) had abnormal chromosome findings, with Down's syndrome noted in 31 of the patients. Twenty-five patients (4.2%) were diagnosed with a single gene disorder while mental retardation was noted in other family members and may indicate possible multifactorial causes in 64 patients (10.8%). An environmental insult was noted in 170 patients (28.6%); unexplained birth defects in 17 patients (2.9%); a specific condition or diagnosis but cause unknown in 27 patients (4.5%); and no diagnosis made in 253 patients (42.5%). Clinical and cytogenetic screening of mentally retarded patients for the fragile-X syndrome and other causes of mental retardation is helpful in identifying individuals and their families who may benefit from genetic services such as counseling and treatment. This study was performed over an approximate 2 year period from 1987 to 1989.

Adolescent↗
PubMed1993

Anthropometric and craniofacial patterns in mentally retarded males with emphasis on the fragile X syndrome.

Anthropometric and craniofacial profile patterns indicating the percent difference from the overall mean were developed on 34 physical parameters with 31 white, mentally retarded males (23 adults and 8 children) with the fra(X) syndrome matched for age with 31 white, mentally retarded males without a known cause of their retardation. The fra(X) syndrome males consistently showed larger dimensions for all anthropometric variables, with significant differences for height, sitting height, arm span, hand length, middle finger length, hand breadth, foot length, foot breadth, and testicular volume. A craniofacial pattern did emerge between the two groups of mentally retarded males, but with overlap of several variables. Significant differences were noted for head circumference, head breadth, lower face height, bizygomatic diameter, inner canthal distance, ear length and ear width, with the fra(X) syndrome males having larger head dimensions (head circumference, head breadth, head length, face height and lower face height), but smaller measurements for minimal frontal diameter, bizygomatic diameter, bigonial diameter, and inner canthal distance. Several significant correlations were found with the variables for both mentally retarded males with and without the fra(X) syndrome. In a combined anthropometric and craniofacial profile of 19 variables comparing 26 white fra(X) syndrome males (13 with high expression (> 30%) and 13 with low expression (< 30%), but matched for age), a relatively flat profile was observed with no significant differences for any of the variables. Generally, fra(X) syndrome males with increased fragile X chromosome expression have larger amplifications of the CGG trinucleotide repeat of the FMR-1 gene. No physical differences were detectable in our study between fra(X) males with high expression and apparently larger amplifications of the CGG trinucleotide repeats compared with those patients with low expression. Our research illustrates the use of anthropometry in identifying differences between mentally retarded males with or without the fra(X) syndrome and offers a comprehensive approach for screening males for the fra(X) syndrome and selecting those individuals for cytogenetic and/or molecular genetic testing.

Adolescent↗
PubMed1993

Clinical and molecular studies in fragile X patients with a Prader-Willi-like phenotype.

A special subphenotype of the fragile X syndrome is reported which is characterised by extreme obesity with a full, round face, small, broad hands/feet, and regional skin hyperpigmentation. It resembles the Prader-Willi syndrome (PWS) and might therefore be named 'Prader-Willi-like'. Unlike the PWS, these PW-like fragile X patients lack the neonatal hypotonia with feeding problems during infancy followed by hyperphagia from toddlerhood. We describe five new fragile X patients and present a clinical update of three previously described patients with the PW-like phenotype. In one family, segregation of either the classical Martin-Bell or the PW-like phenotype was observed and in another family there was repeated transmission of the PW-like phenotype. Previously, one of the patients had been misdiagnosed as having classical PWS, based on clinical findings. Molecular studies of the FMR-1 gene showed the typical full mutations as seen in fragile X syndrome males. Molecular analysis of the 15q11-13 region, which is deleted in the majority of classical PWS patients, did not show any detectable abnormalities. In a group of 26 patients with suspected Prader-Willi syndrome but without detectable molecular abnormalities of chromosome 15, one fragile X patient was found. These clinical and molecular findings illustrate the necessity to perform DNA analysis of the FMR-1 gene in mentally retarded patients presenting with a PW phenotype but without the PWS specific cytogenetic/molecular abnormalities of chromosome 15.

Adolescent↗