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B T Darras

Publications and source records attributed to B T Darras.

48 records · Page 3Linked to original sources
PubMed1988

Normal human genomic restriction-fragment patterns and polymorphisms revealed by hybridization with the entire dystrophin cDNA.

Since the complete cDNA for the gene that causes X-linked recessive Duchenne/Becker muscular dystrophy (DMD/BMD) when mutated or deleted has recently been cloned and made generally available, DNA-based diagnostic studies of affected males and their families have entered into a new era. This communication sets forth the standard patterns of restriction fragments that are detected when normal human DNA cleaved with either HindIII or BglII is hybridized with seven contiguous segments comprising the entire 14-kb cDNA. Collectively, the more than 60 restriction fragments allow visualization of approximately 350 (HindIII) to 400 (BglII) kbp. This corresponds to the exon-containing one-fifth of the total genomic length of this gene, including the 3' untranslated region. Twelve two-allele restriction-site polymorphisms that span the entire length of the gene were detected with the cDNA probes and allele frequencies determined. A diagnostic approach is proposed that starts with deletion screening of DNA from male probands, includes carrier detection based on relative fragment intensities, and extends to RFLP detection using the same autoradiographs prepared for deletion screening. Our results on deletion analysis of 32 DMD/BMD families are presented in an accompanying paper.

DNA↗
PubMed1988

Intragenic deletions in 21 Duchenne muscular dystrophy (DMD)/Becker muscular dystrophy (BMD) families studied with the dystrophin cDNA: location of breakpoints on HindIII and BglII exon-containing fragment maps, meiotic and mitotic origin of the mutations.

Following the strategy outlined in an accompanying paper, we studied 32 X-linked muscular dystrophy families (29 Duchenne [DMD] and three Becker [BMD] type) for abnormalities of HindIII and BglII fragments detected by the entire dystrophin cDNA. Twenty-one different single-intragenic deletions, and no duplications, were identified. The deletion endpoints were precisely mapped on the published HindIII fragment map. Detailed analysis of overlapping deletions led to clarification of the fragment order for some previously unsettled regions of the HindIII map and to the construction of a partial map of exon-containing BglII fragments. For the regions involved in deletions, the corresponding HindIII and BglIII fragments could be identified. Noncontiguous comigrating fragments were detected in two regions by careful analysis of the patterns in deletion patients. Four of the 21 deletions generated novel restriction fragments that facilitated detection of female carriers in these families. Twelve of the deletions had a breakpoint in one of the two large introns known to be the sites of breakpoint clusters. By combining deletions and RFLP analyses, we unequivocally identified the gamete that first carried the mutation in 13 families: eight oocytes and five sperm. Germ-line mosaicism previously detected in one male was confirmed by cDNA studies. In two additional families gonadal mosaicism was found in females. As evidence is accumulating for frequent mitotic origin of these deletion mutations, this phenomenon has to be considered when postulating mutational mechanisms and in genetic counseling of DMD/BMD families.

Bacterial Proteins↗
PubMed1987

Prenatal diagnosis and detection of carriers with DNA probes in Duchenne's muscular dystrophy.

We performed genetic analyses for the prenatal diagnosis of Duchenne's muscular dystrophy and detection of the carrier state in five families with seven pregnancies at risk for the disease. As genetic markers for the disorder, we used DNA-sequence polymorphisms detected with 12 different DNA probes derived from the vicinity of the Duchenne's muscular dystrophy locus or from within the gene, on the X chromosome. One male fetus of a proved carrier mother was predicted to be unaffected, and this was confirmed after birth. Another male fetus was predicted to be unaffected (probability, 95 percent or greater), although a crossover event had been identified in a region of the X chromosome thought to be distal to the Duchenne gene. Unfortunately, an elevated serum creatine kinase level after birth indicated that the infant had inherited the Duchenne mutation. Three male fetuses predicted to be affected with 66 percent or 95 percent probabilities were aborted, and the presence of the DNA-marker alleles was confirmed in fetal tissues. In one family, in which the maternal grandparents were unavailable, the initial genetic interpretation had to be revised after a second male fetus was analyzed with intragenic probes. Our experience suggests that despite the large number of intragenic and flanking DNA polymorphisms available, uncertainties often remain in the prenatal diagnosis of Duchenne's muscular dystrophy. Pitfalls are presented by the large size of the region in which Duchenne's mutations can occur. Crossover events in this region, which result in an exchange of DNA between two X chromosomes, can render DNA-marker studies inaccurate. Also, an autosomal recessive mutation can produce the same clinical picture.

Creatine Kinase↗
PubMed1987

Congenital adrenal hypoplasia, myopathy, and glycerol kinase deficiency: molecular genetic evidence for deletions.

Glycerol kinase deficiency (GKD) is an X-linked recessive trait that occurs in association with congenital adrenal hypoplasia (AH) and developmental delay with or without congenital dystrophic myopathy. Several such patients have recently been reported to have cytological deletions of chromosome region Xp21 and/or of DNA markers that map near the locus for Duchenne muscular dystrophy (DMD) in band Xp21. We have examined the initial family reported in the literature and, using prometaphase chromosome studies and Southern blot analysis with 13 different DNA probes derived from band Xp21, have found no deletions within this region of the X chromosome. When DNA samples from six other unrelated affected males were analyzed, four of them were found to have different-size deletions within Xp21. Thus, the form of GKD associated with AH and dystrophic myopathy exhibits significant genetic heterogeneity at the DNA level. No deletions were detected in two patients with isolated GK deficiency. Comparison of our molecular studies of unrelated patients with deletions of DNA segments allows us to define the region of Xp21 (between probes J-Bir and L1.4) that most likely contains the genes for GKD and AH. This location is distal to the DMD locus. The patients with progressive muscular dystrophy tended to have larger deletions that include markers known to derive from the DMD locus, while GKD/AH/dystrophic-myopathy patients without current evidence of deletion seemed to have a milder, nonprogressive form of congenital myopathy.

Abnormalities, Multiple↗
PubMed1986

Globoid cell leukodystrophy: cranial computed tomography and evoked potentials.

The evoked potentials and cranial computed tomographic (CT) scan findings in a case of early infantile globoid cell leukodystrophy are presented. The brain stem auditory evoked responses (BAERs) and the flash visual evoked potentials (VEPs) were abnormal. Repeated cranial CT scans showed multiple areas of increased attenuation and progressive cerebral atrophy. These evoked potential and CT scan patterns occurring concomitantly in an infant are suggestive of globoid cell leukodystrophy.

Electroencephalography↗
PubMed1986

Familial amyloidosis with cranial neuropathy and corneal lattice dystrophy.

A 64-year-old woman had bilateral facial weakness, mild peripheral neuropathy, incoordination, and impaired balance. A corneal transplant had been performed for corneal lattice dystrophy. Sural nerve biopsy showed mild axonal neuropathy with deposits of amyloid in the perineurium. Histochemical studies showed amyloid protein AA in the nerve, but not in cornea or muscle.

Adult↗
PubMedDate not supplied

Intermittent dystonia in Hartnup disease.

A 6-month-old girl developed intermittent dystonic posture of the legs and eczematous dermatitis without ataxia. Qualitative and quantitative urine amino acid testing confirmed the diagnosis of Hartnup disease. Cranial computed tomography, electroencephalogram, electromyogram/nerve conduction study, posterior tibial somatosensory evoked potentials, 24-hour electroencephalographic telemetry, and metrizamide myelogram were normal. Spinal fluid hydroxy-indoleacetic acid concentration was less than or equal to 2 S.D. of normal; oral tryptophan loading (70 mg/kg) resulted in a two-fold rise in cerebrospinal fluid 5-hydroxy-indoleacetic acid concentration. Tryptophan administered alone or with nicotinic acid failed to improve the dystonia; however, trihexyphenidyl (1-2 mg/kg/day) dramatically improved it. Hartnup disease should be considered in children with unexplained dystonia.

Brain Chemistry↗
PubMedDate not supplied

Eastern equine encephalitis presenting with a focal brain lesion.

Eastern equine encephalitis (EEE) virus causes a severe meningoencephalitis with high morbidity and mortality. Despite numerous clinical reports of EEE, there are only 11 patients in whom cranial computed tomographic (CT) findings are described. In 6 patients, CT was normal and in 5 patients diffuse edema was present; none had a focal brain lesion. Based on these reports, it has been suggested that focal findings on CT support the diagnosis of herpes simplex encephalitis rather than EEE. The first patient with serologically-confirmed EEE and a focal lesion demonstrated by cranial CT and magnetic resonance imaging is described; these findings underscore the importance of including EEE in the differential diagnosis of encephalitides that can cause focal brain lesions on neuroimaging.

Brain↗
PubMedDate not supplied

Analysis of deletions in DNA from patients with Becker and Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic disorder for which the biochemical defect is as yet unknown. Recently, two cloned segments of human X-chromosome DNA have been described which detect structural alterations within or near the genetic locus responsible for the disorder. Both of these cloned segments were described as tightly linked to the locus and were capable of detecting deletions in the DNA of boys affected with DMD. In an attempt to determine more precisely the occurrence of these deletions within a large population of DMD patients and the accuracy of one of the segments, DXS164 (pERT87), in determining the inheritance of the DMD X chromosome, the subclones 1, 8 and 15 were made available to many investigators throughout the world. Here we describe the combined results of more than 20 research laboratories with respect to the occurrence of deletions at the DXS164 locus in DNA samples isolated from patients with DMD and Becker muscular dystrophy (BMD). The results indicate that the DXS164 locus apparently recombines with DMD 5% of the time, but is probably located between independent sites of mutation which yield DMD. The breakpoints of some deletions are delineated within the DXS164 locus, and it is evident that the deletions at the DMD locus are frequent and extremely large.

Chromosome Deletion↗
PubMedDate not supplied

A partial deletion of the muscular dystrophy gene transmitted twice by an unaffected male.

A gene of unknown function located in band Xp21 on the short arm of the human X chromosome gives rise to X-linked recessive muscular dystrophy, of either Duchenne or Becker type, when mutated. The gene encodes a large muscle-specific transcript of about 14 kilobases (kb) and its genomic size extends over more than 1,800 kb. The high mutation rate (about 10(-4) per generation) is likely to result from the large target size. Submicroscopic deletions, detectable with one or more of the dozen cloned DNA probes available for regions within the gene, constitute a significant proportion of the mutations. Because no such deletions have been found in normal individuals, it is assumed that intragenic deletions are the molecular basis of the mutations. The origin of deletions can be traced in families. With sufficient data collected, it will soon be possible to answer questions about the relative frequencies of mutations in male and female gametogenesis and about the timing of mutational events in mitotic or meiotic stages of germ cell development. We have studied a four generation family containing males who have Duchenne muscular dystrophy due to deletion of the sequence recognized by intragenic probe J-Bir. The deletion was present in two of five daughters of a woman who herself did not have the deletion. Haplotype analysis on 15 members of this family using nine informative restriction fragment length polymorphism (RFLP) markers indicated that the J-Bir deletion chromosome was transmitted from the unaffected father.

Chromosome Deletion↗
PubMedDate not supplied

Viral and bacterial pathogens of suspected sepsis in young infants.

Clinical and laboratory data of 27 previously normal, healthy infants 2 months of age or less who were hospitalized for suspected sepsis during a 1-year period were reviewed. Results of bacterial cultures and viral studies revealed enteroviruses (seven echoviruses, one coxsackievirus) to be the predominant pathogens identified. Other viruses identified were one each of adenovirus, untypeable hemadsorbing virus and respiratory syncytial virus. Group B streptococcal and enterococcal bacteremia and salmonellosis were diagnosed in one case each. Gram-negative bacillary urinary tract infections occurred in two patients. No pathogens were identified in 11 patients. Although these data indicate an important role for enteroviruses in this syndrome during summer and fall, we believe that the occult bacteremia found in 7% of our patients justifies initial antibiotic therapy in very young infants with suspected sepsis.

Anti-Bacterial Agents↗