Biomedical subjects

Thomas M Bosley

Publications and source records attributed to Thomas M Bosley.

13 recordsLinked to original sources

PubMed2007

Epidemiology of giant-cell arteritis in an Arab population: a 22-year study.

OBJECTIVE: To study the epidemiology of biopsy-proven giant-cell arteritis (GCA) in an Arab population with clinical features suggestive of GCA. METHODS: Clinical records of 102 patients who underwent temporal artery biopsy (TAB) at King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia from January 1983 to December 2004 were reviewed. RESULTS: Among the 56 men and 46 women who had TAB, 7 (6.8%) had biopsy-proven GCA. The mean (SD) age of the biopsy-positive group (71.7 (8.6) years) was higher than in the biopsy-negative group (65 (9.8) years; p = 0.005). None of the untreated patients with a negative TAB developed additional symptoms that are typical of GCA. CONCLUSION: The small absolute number of biopsy-proven cases of GCA implies a relatively low incidence of GCA in Arab population, confirming previous observations that GCA occurs primarily in the Caucasian population.

Aged↗

PubMed2006

Neurological features of congenital fibrosis of the extraocular muscles type 2 with mutations in PHOX2A.

Congenital fibrosis of the extraocular muscles type 2 (CFEOM2) is a complex strabismus syndrome that results from mutations in the homeodomain transcription factor PHOX2A. To define the clinical and neuroimaging features of patients with this autosomal recessive syndrome, we studied 15 patients with genetically defined CFEOM2. All patients underwent full neurological, neuro-ophthalmological and orthoptic assessments. Twelve patients had pupillary pharmacological testing and nine had 3.0 tesla MRI of the brain, brainstem and orbits. Patients were born with severe bilateral ptosis and exotropia with almost complete bilateral absence of adduction, elevation, depression and intorsion. Variable abduction was present prior to strabismus surgery in 14 patients, and central ocular motility reflexes (smooth pursuit, saccades, vestibulo-ocular reflex and optokinetic reflex) were intact except for convergence. Pupillary light and near reflexes were not present, but irises were anatomically normal and responded to pupillary pharmacology. Neuroimaging of brain and brainstem was remarkable for the anatomical absence of cranial nerve (CN) 3 and probably CN 4 bilaterally. Therefore, the CFEOM2 phenotype and neuroimaging are both consistent with the congenital absence of CNs 3 and 4. Additional features included presence of most central ocular motility reflexes, a central lack of pupillary responsiveness of uncertain aetiology and modest phenotypic variability that does not correlate with specific PHOX2A mutations. Clinical presentation, neuroimaging and Phox2a-/- animal models all support the concept that CFEOM2 is a primary neurogenic abnormality with secondary myopathic changes.

Adolescent↗

PubMed2006

Mitochondrial abnormalities in patients with primary open-angle glaucoma.

PURPOSE: Primary open-angle glaucoma (POAG) is the second most common cause of blindness. It has been linked to mutations in the myocilin (MYOC) and optineurin (OPTN) genes, although mutations have been found in <5% of patients. The pathologic mechanism(s) of POAG remain unknown but may include retinal ganglion cell apoptosis, which causes progressive damage to axons at the optic nerve head. METHODS: In 27 patients with definite POAG, the MYOC and OPTN genes were sequenced, the entire mitochondrial (mt)DNA coding region was sequenced, relative mtDNA content was investigated, and mitochondrial respiratory function was assessed. RESULTS: Only three benign polymorphisms were identified in MYOC and OPTN in patients with POAG and in control subjects. Conversely, 27 different novel nonsynonymous mtDNA changes were found, only in patients with POAG (not control subjects), 22 of which (found in 14 patients) were potentially pathogenic. Unlike Leber hereditary optic neuropathy, most mtDNA sequence alterations in patients with POAG were transversions-sequence changes that alter the purine/pyrimidine orientation and imply oxidative stress. mtDNA content was relatively increased in 17 patients with POAG compared with age-matched control subjects, also implying a possible response to oxidative stress. Mean mitochondrial respiratory activity was decreased by 21% in patients with glaucoma compared with control subjects (P<0.001). CONCLUSIONS: These results reveal a spectrum of mitochondrial abnormalities in patients with POAG, implicating oxidative stress and implying that mitochondria dysfunction may be a risk factor for POAG. This concept may open up new experimental and therapeutic opportunities.

Adult↗

PubMed2006

Mitochondrial abnormalities in patients with LHON-like optic neuropathies.

PURPOSE: To investigate certain biochemical and molecular characteristics of mitochondria in patients with Leber hereditary optic neuropathy (LHON)-like optic neuropathies. METHODS: Patients who had LHON-like optic neuropathies in both eyes were selected from neuro-ophthalmology clinics. Evaluation included clinical examination, neuroimaging, and assessment of several mitochondrial parameters in the blood, including sequencing the entire mitochondrial (mt)DNA coding region, measuring relative mtDNA content, studying mitochondrial respiratory function in some patients, and sequencing the OPA1 and OPA3 genes. RESULTS: Thirty-five patients (21 men and 14 women; average age at onset 19.0 +/- 8.7 years) met inclusion and exclusion criteria for LHON-like optic neuropathies with median visual acuity approximately 20/200. Other hereditary retinopathies and optic neuropathies were unlikely because of inclusion and exclusion criteria, because ERGs were normal, and because no patient had pathogenic sequence changes in the OPA1 or OPA3 genes. Compared with control subjects, these patients had more potentially pathogenic nonsynonymous mtDNA changes, greater relative mtDNA content (P < 0.001), and less mitochondrial respiratory activity (P < 0.001). Only six patients (17%) had primary LHON mutations; however, even the 29 patients without primary LHON mutations had significant evidence of mitochondrial abnormalities. Mitochondrial haplogroup distribution was similar in patients and control subjects. CONCLUSIONS: Primary LHON mutations are less common in patients with LHON-like optic neuropathy selected from a clinical setting than in patients with LHON from multigenerational families. The results suggest that mitochondrial dysfunction plays a role in this type of optic neuropathy whether or not primary LHON mutations are present. This information has implications for diagnostic testing and for future investigations into mechanisms of disease.

Adolescent↗

PubMed2005

Homozygous HOXA1 mutations disrupt human brainstem, inner ear, cardiovascular and cognitive development.

We identified homozygous truncating mutations in HOXA1 in three genetically isolated human populations. The resulting phenotype includes horizontal gaze abnormalities, deafness, facial weakness, hypoventilation, vascular malformations of the internal carotid arteries and cardiac outflow tract, mental retardation and autism spectrum disorder. This is the first report to our knowledge of viable homozygous truncating mutations in any human HOX gene and of a mendelian disorder resulting from mutations in a human HOX gene critical for development of the central nervous system.

Autistic Disorder↗

PubMed2005

Mitochondrial T9957C mutation in association with NAION and seizures but not MELAS.

PURPOSE: To assess the functional significance of the mitochondrial nt-9957 mutation in a man with non-arteritic ischemic optic neuropathy (NAION). This nt-9957 mutation has been previously reported in association with mitochondrial encephalopathy, lactic acidosis, and stroke-like events (MELAS). METHODS: The patient was examined clinically and with magnetic resonance imaging and spectroscopy. The entire coding region of the mitochondrial genome was sequenced, and mitochondrial function was assessed by flow cytometry after staining with fluorescent dihydroethidium. RESULTS: This 76-year-old man had optic nerve disease bilaterally and seizures, but no clinical or radiological evidence of MELAS. He had no mitochondrial DNA mutation other than the 9957. Functional testing revealed a severe defect in mitochondrial complex III activity. CONCLUSIONS: This patient had a mitochondrial functional deficit consistent with his 9957 mutation. It seems quite likely that this mutation may be responsible for optic nerve and brain injuries.

Case-Control Studies↗

PubMed2005

Detection of mitochondrial respiratory dysfunction in circulating lymphocytes using resazurin.

CONTEXT: Laboratory methods currently available for detecting mitochondrial respiratory dysfunction are labor-intensive, require large amounts of isolated mitochondrial protein, invasive (require a skeletal muscle biopsy), and usually produce conflicting results. OBJECTIVE: To develop a rapid, reliable, and noninvasive method for detecting oxidative phosphorylation activity without the need to isolate mitochondrial fractions. DESIGN: Lymphocytes from 6 patients with mitochondrial disorders (3 with mitochondrial myopathy and 3 with Leber hereditary optic neuropathy) and 51 normal control subjects were incubated with 6 microM resazurin without and with mitochondrial inhibition by amiodarone (200 microM), and the fluorescence intensity resulting from resazurin reduction was monitored spectrofluorometrically over time. Mitochondrial respiratory activity was calculated as the difference between uninhibited and inhibited measurements. RESULTS: Mitochondrial respiratory activity was established for 51 normal control subjects and was decreased in all 6 patients with mitochondrial syndromes. Mitochondrial respiratory activity values for patients 1 through 6 compared to the control group after 240 minutes' incubation with resazurin were 55%, 71%, 49%, 61%, 68%, and 59%, respectively (mean mitochondrial respiratory activity of patients, 13.6% or 60.5% of control mean; P < .001). CONCLUSION: This resazurin-based technique proved to be a fast and reproducible method for quantifying mitochondrial activity and identifying respiratory functional defects in patients with mitochondrial disorders.

Adolescent↗

PubMed2004

Mitochondrial DNA nucleotide changes in non-arteritic ischemic optic neuropathy.

The authors sequenced the entire mitochondrial DNA coding region in a group of 19 patients with non-arteritic anterior ischemic optic neuropathy (NAION) and in 100 controls. Synonymous and nonsynonymous nucleotide changes were more common in NAION patients (p < 0.001). Twelve of these (11 novel) were potentially pathologic, nine of which altered moderately or highly conserved amino acids in the functional domain of the affected protein. Mitochondrial malfunction may be a risk factor for NAION.

Adult↗

PubMed2004

Mutations in a human ROBO gene disrupt hindbrain axon pathway crossing and morphogenesis.

The mechanisms controlling axon guidance are of fundamental importance in understanding brain development. Growing corticospinal and somatosensory axons cross the midline in the medulla to reach their targets and thus form the basis of contralateral motor control and sensory input. The motor and sensory projections appeared uncrossed in patients with horizontal gaze palsy with progressive scoliosis (HGPPS). In patients affected with HGPPS, we identified mutations in the ROBO3 gene, which shares homology with roundabout genes important in axon guidance in developing Drosophila, zebrafish, and mouse. Like its murine homolog Rig1/Robo3, but unlike other Robo proteins, ROBO3 is required for hindbrain axon midline crossing.

Adult↗

PubMed2004

Identification of KIF21A mutations as a rare cause of congenital fibrosis of the extraocular muscles type 3 (CFEOM3).

PURPOSE: Three congenital fibrosis of the extraocular muscles phenotypes (CFEOM1-3) have been identified. Each represents a specific form of paralytic strabismus characterized by congenital restrictive ophthalmoplegia, often with accompanying ptosis. It has been demonstrated that CFEOM1 results from mutations in KIF21A and CFEOM2 from mutations in PHOX2A. This study was conducted to determine the incidence of KIF21A and PHOX2A mutations among individuals with the third CFEOM phenotype, CFEOM3. METHODS: All pedigrees and sporadic individuals with CFEOM3 in the authors' database were identified, whether the pedigrees were linked or consistent with linkage to the FEOM1, FEOM2, and/or FEOM3 loci was determined, and the appropriate pedigrees and the sporadic individuals were screened for mutations in KIF21A and PHOX2A. RESULTS: Twelve CFEOM3 pedigrees and 10 CFEOM3 sporadic individuals were identified in the database. The structures of eight of the pedigrees permitted the generation of meaningful linkage data. KIF21A was screened in 17 probands, and mutations were identified in two CFEOM3 pedigrees. One pedigree harbored a novel mutation (2841G-->A, M947I) and one harbored the most common and recurrent of the CFEOM1 mutations identified previously (2860C-->T, R954W). None of CFEOM3 pedigrees or sporadic individuals harbored mutations in PHOX2A. CONCLUSIONS: The results demonstrate that KIF21A mutations are a rare cause of CFEOM3 and that KIF21A mutations can be nonpenetrant. Although KIF21A is the first gene to be associated with CFEOM3, the results imply that mutations in the unidentified FEOM3 gene are the more common cause of this phenotype.

DNA Mutational Analysis↗

PubMed2003

Silicone nasolacrimal intubation with mitomycin-C: a prospective, randomized, double-masked study.

OBJECTIVE: To determine if mitomycin-C (MMC) application during silicone intubation (SI) can effectively substitute for dacryocystorhinostomy (DCR) or Jones tube insertion. DESIGN: A prospective, randomized, double-masked study. PARTICIPANTS: Twenty-four patients (7 males, 17 females; aged 2-69 years) with 27 eyes (three bilateral cases) with an obstructed lacrimal system who were candidates for DCR or Jones tube. METHODS: All study patients underwent SI with application in a randomized, double-masked fashion of MMC or placebo, with the former receiving 0.2 mg/ml MMC for 2 minutes before SI. MAIN OUTCOME MEASURES: Clinical assessment of tearing and discharge; Schirmer I and II tests at 1, 3, 6, and 12 months; and the need for eventual DCR or Jones tube insertion. RESULTS: Follow-up ranged from 13 to 23 months (mean, 18 months; median, 17 months). Seven of the 12 eyes in the MMC group and 8 of the 15 eyes in the placebo group had a successful outcome and remained symptom free. The difference was not statistically significant (P = 0.79). Dacryocystorhinostomy or Jones tube was performed in five eyes in the MMC group and in seven eyes in the placebo group 3 to 18 months later; all had successful outcome and no complications. Untoward effects of MMC application included a slit canaliculus and a transient conjunctival injection. A successful outcome using this combined technique does not appear to correlate with age, gender, laterality, and intraoperative bleeding observed at the punctum or for the duration of symptoms. CONCLUSIONS: Mitomycin-C application during SI did not benefit outcome. Complications from such application were mild and infrequent.

Adolescent↗

PubMed2003

Orbit deformities in craniofacial neurofibromatosis type 1.

BACKGROUND AND PURPOSE: The possible relationship of orbit deformities in neurofibromatosis type 1 (NF1) to plexiform neurofibromas (PNFs) have not been fully elucidated. Our purpose was to review orbital changes in patients with craniofacial NF1. METHODS: We retrospectively reviewed CT and MR imaging abnormalities of the orbit in 31 patients (18 male, 13 female; mean age, 14 years; age range 1-40 years) with craniofacial NF1. RESULTS: Orbital abnormalities were documented in 24 patients. Six had optic nerve gliomas with enlarged optic canals. Twenty had PNFs in the orbit or contiguous to the anterior skull. The posterior orbit was distorted by encroachment from an expanded middle cranial fossa in 13 patients, and 18 had enlargement of the orbital rim. Other changes included focal decalcification or remodeling of orbital walls adjacent to PNFs in 18 patients and enlargement of cranial foramina resulting from tumor infiltration of sensory nerves in 16. These orbital deformities were sometimes progressive and always associated with orbital infiltration by PNFs. CONCLUSION: In our patients with craniofacial neurofibromatosis, bony orbital deformity occurred frequently and always with an optic nerve glioma or orbital PNF. PNFs were associated with orbital-bone changes in four patterns: expansion of the middle cranial fossa into the posterior orbit, enlargement of the orbital rim, bone erosion and decalcification by contiguous tumor, and enlargement of the cranial foramina. Orbital changes support the concept of secondary dysplasia, in which interaction of PNFs with the developing skull is a major component of the multifaceted craniofacial changes possible with NF1.

Adolescent↗

PubMed2002

Reassessment of sphenoid dysplasia associated with neurofibromatosis type 1.

BACKGROUND AND PURPOSE: Sphenoid dysplasia associated with neurofibromatosis type 1 is classically thought to be primarily related to abnormal development of the sphenoid bone. We investigated the possibility that these changes may be progressive. METHODS: We conducted a retrospective review of sphenoid bone changes in all patients with craniofacial neurofibromatosis type 1 who had undergone CT (31 patients) and MR imaging (seven patients) at our facility. A review of repeat images of 20 patients permitted analysis of progressive sphenoid bone changes. RESULTS: Eighteen patients had abnormalities of the sphenoid wings, 13 of whom also had enlargement of the middle cranial fossa compatible with descriptions of classic sphenoid dysplasia. All the patients with sphenoid dysplasia had neurofibromas in the ipsilateral superficial temporal fossa that were often contiguous with a radiologically abnormal temporo-squamosal suture. All except one had tumor infiltration in the deep orbit, contiguous with the sphenoid wings. Four patients had radiologic evidence of progressive sphenoid bone changes over time. CONCLUSION: The origin of sphenoid bone changes may be multifactorial. A modified concept of sphenoid dysplasia is proposed that emphasizes interaction between neurofibromas and sphenoid bone during skull development.

Adolescent↗