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Ian M MacDonald

Publications and source records attributed to Ian M MacDonald.

At least 19 recordsLinked to original sources
PubMed2006

Choroideremia: variability of clinical and electrophysiological characteristics and first report of a negative electroretinogram.

PURPOSE: To analyze the variability of clinical and electrophysiological characteristics in X-linked choroideremia and provide the first report of a negative electroretinogram in choroideremia. DESIGN: Retrospective study. PARTICIPANTS: The records of 18 male patients with choroideremia and 8 female carriers were evaluated. METHODS: The data were reviewed regarding visual acuity (VA), color vision, perimetry, fundus autofluorescence, and full-field electroretinography (according to standards of the International Society for Clinical Electrophysiology of Vision). MAIN OUTCOME MEASURES: Morphological and functional phenotype characteristics, fundus autofluorescence, electroretinography, and Rab escort protein 1 (REP-1) mutations. RESULTS: Four unrelated families with choroideremia (9 affected males, 7 carriers) and 10 unrelated individuals (9 affected males, 1 carrier) were included. Mutational analysis, performed in 2 families and 3 individual males, revealed REP-1 mutations in all except 1 male. The age of the males ranged from 5.9 to 63.0 years (mean, 33.9), and VA ranged from hand movements to 1.0 (median, 0.7). Fundus autofluorescence (n = 7) showed defects in the retinal pigment epithelium in all males. Electroretinography (n = 13) was almost undetectable in 6 males and reduced in 6, indicating a rod-cone dystrophy. A further male showed a negative electroretinogram, with a b:a wave ratio of 0.5. Visual acuity of the 8 carriers (age, 4.8-56.8 years [mean, 24.0]) ranged from light perception to 1.2 (median, 1.0). Light perception was present in 1 carrier manifesting choroideremia with distinct chorioretinal atrophy. Pigmentary stippling, seen in the other carriers, was seen in fundus autofluorescence (n = 1) with a distinct speckled pattern. Electroretinograms were normal in 6 of 7 and reduced in the manifesting carrier. Defects in color vision and visual field were found in affected males and in the female carriers. CONCLUSIONS: The phenotype of choroideremia presents with high variability. In addition to the previously reported findings, we observed a negative electroretinogram, indicating a postreceptoral retinal dysfunction, in 1 affected male; severe course of choroideremia with early blindness in 1 manifesting carrier; color vision deficits in the majority of affected males and carriers; and characteristic alterations in fundus autofluorescence.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Remodeling of the human retina in choroideremia: rab escort protein 1 (REP-1) mutations.

PURPOSE: To characterize in detail the disease expression in choroideremia (CHM), a blinding X-linked disease of the retina caused by loss-of-function mutations in Rab Escort Protein 1 (REP-1). CHM is readily diagnosed in the clinic and by molecular testing but has lacked an animal model to test hypotheses and therapeutics. The recent report of a mouse model for CHM prompts the need for reassessment of the human disease in anticipation of treatment initiatives. METHODS: CHM hemizygotes with REP-1 mutations, spanning an age range of 7 decades, were studied with in vivo microscopy by optical coherence tomography. RESULTS: The disease expression was complex. Earliest stages involved a thickening of the retina that was otherwise normally laminated. Loss of photoreceptors, either independent or associated with retinal pigment epithelium (RPE) depigmentation, was followed by disorganization and further thickening of the retina with interlaminar bridges. The dysmorphic retina then slowly thinned over decades. Laminopathy occurred first in more peripheral rod-rich regions and later in the cone-rich fovea. CONCLUSIONS: The CHM disease sequence involves detectable retinal thickening, which may be due to Müller cell activation and hypertrophy from photoreceptor stress. Photoreceptor degeneration, RPE depigmentation, and retinal remodeling follow. The results represent in vivo evidence in humans for retinal remodeling and provide a marker for the earliest stage of this response to genetic retinal disease. For CHM and other candidate human retinopathies considered for therapy, there is now a framework for making informed decisions about timing, retinal location, and potential value of treatment.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Genetic aspects of age-related macular degeneration.

Age-related macular degeneration (AMD) is a complex phenotype that has multiple causes, including genetic. This paper reviews pertinent single-gene disorders, polymorphisms in the human genome that modify disease severity, and maculopathies that provide insight into the pathogenesis of AMD and the function of the normal macula. The availability of DNA-based analysis for certain genes will likely increase the demand for genetic counselling of patients and families with AMD. Better knowledge of risks should help prevent blindness in these families.

ATP-Binding Cassette Transporters↗
PubMed2005

A new case of oculoectodermal syndrome.

An 11-month-old infant girl presented with right-sided features of aplasia cutis congenita of the scalp, unilateral epibulbar dermoids, eccentric pupil, coloboma of the right upper eyelid, and depigmentation of the fundus surrounding the right optic nerve. These findings were similar to the oculoectodermal syndrome reported by other clinicians and researchers.

Coloboma↗
PubMed2004

Phenotypic and molecular assessment of seven patients with 6p25 deletion syndrome: relevance to ocular dysgenesis and hearing impairment.

BACKGROUND: Thirty-nine patients have been described with deletions involving chromosome 6p25. However, relatively few of these deletions have had molecular characterization. Common phenotypes of 6p25 deletion syndrome patients include hydrocephalus, hearing loss, and ocular, craniofacial, skeletal, cardiac, and renal malformations. Molecular characterization of deletions can identify genes that are responsible for these phenotypes. METHODS: We report the clinical phenotype of seven patients with terminal deletions of chromosome 6p25 and compare them to previously reported patients. Molecular characterization of the deletions was performed using polymorphic marker analysis to determine the extents of the deletions in these seven 6p25 deletion syndrome patients. RESULTS: Our results, and previous data, show that ocular dysgenesis and hearing impairment are the two most highly penetrant phenotypes of the 6p25 deletion syndrome. While deletion of the forkhead box C1 gene (FOXC1) probably underlies the ocular dysgenesis, no gene in this region is known to be involved in hearing impairment. CONCLUSIONS: Ocular dysgenesis and hearing impairment are the two most common phenotypes of 6p25 deletion syndrome. We conclude that a locus for dominant hearing loss is present at 6p25 and that this locus is restricted to a region distal to D6S1617. Molecular characterization of more 6p25 deletion patients will aid in refinement of this locus and the identification of a gene involved in dominant hearing loss.

Abnormalities, Multiple↗
PubMed2004

Genetics and ARMD.

Explore the source record for details and available documents.

ATP-Binding Cassette Transporters↗
PubMed2004

Detection of localized retinal dysfunction in a choroideremia carrier.

PURPOSE: To investigate severe unilateral vision loss in a choroideremia carrier. DESIGN: Case report. METHODS: Ocular examination, genetic testing, Humphrey visual fields, full-field and multifocal (mf) electroretinogram (ERG) tests were used to study a family with choroideremia. RESULTS: In a carrier with unilateral central vision loss, mfERG showed severely reduced amplitudes which correlated with a band of retinal pigment epithelial and choroidal atrophy in the macula, a dense central scotoma on Humphrey visual fields testing, and decreased ERG amplitudes. CONCLUSIONS: Multifocal ERG may be a sensitive tool to measure functional abnormalities in choroideremia carriers. Mosaic inactivation of the normal gene may cause expression of the mutation with severe vision loss in choroideremia carriers.

Aged↗
PubMed2004

Strabismus after regional anesthesia for cataract surgery.

BACKGROUND: An adult strabismus clinic in a regional eye centre provided an opportunity to estimate the risk of postoperative diplopia from regional anesthesia after cataract surgery and to describe the management of these patients. METHODS: Retrospective cohort analysis. All cases were referred over a 22-month period (November 1997 to September 1999) for investigation of postoperative diplopia after cataract surgery. The surgical and anesthetic records were reviewed to determine the number and location of injections, and the volume and type of regional anesthesia. The evolution and management of patients' diplopia was studied prospectively. RESULTS: Twenty-one patients (12 women and 9 men aged 63 to 88 [median 76] years) were ascertained with postoperative diplopia. In 11 cases the right eye was affected, and in 10 cases, the left eye. Vertical diplopia occurred most commonly from inferior rectus restriction (16 cases). Three cases resolved without treatment, which indicated that the diplopia was transient. Four patients declined treatment, five required prism in eyeglasses only, and nine required strabismus surgery. One patient required surgery and prism in eyeglasses. Two patients required more than one strabismus operation to relieve the diplopia. For the period of data collection, we estimate the risk of nontransient postoperative diplopia from regional anesthesia as 2.6 cases per 1000 cataract procedures (95% confidence interval 1.9-4.7). INTERPRETATION: Patients should be forewarned of the risk of diplopia after cataract surgery with regional anesthesia. The treatment of the diplopia may require prism in eyeglasses or strabismus surgery or both.

Aged↗
PubMed2004

Choroideremia gene testing.

Choroideremia is a chorioretinal degeneration displaying X-linked recessive inheritance. In recent years, technological advances have increased the accessibility of genetic testing for mutations in the gene that lead to this disorder. The disorder itself, approaches for its detection and the steps and the rationale behind testing are outlined in this review. All mutations in the choroideremia gene result in the truncation or absence of the normal protein product Rab escort protein-1, which is a component of Rab geranylgeranyltransferase, an enzyme complex that mediates correct intracellular vesicular transport. Sequence analysis of the 15 exons of the choroideremia gene and adjacent splice sites is a primary method of mutation detection used by the authors' laboratory, through which a variety of mutations including nonsense mutations, insertions, deletions and splice site alterations have been detected. Alternatively, if no mutations are revealed using this approach, reverse transcription PCR, northern blot analysis or a protein truncation test can be employed to detect aberrantly spliced products. Immunoblot analysis can also be performed to confirm the absence of Rab escort protein-1 in affected males. Deletions create a practical problem in assessing the carrier status of females; linkage analysis with closely linked markers is the most practical approach in these cases.

Adaptor Proteins, Signal Transducing↗
PubMed2003

The use of lymphocytes to screen for oxidative phosphorylation disorders.

Biochemical analysis of oxidative phosphorylation (OXPHOS) disorders is traditionally carried out on muscle biopsies, cultured fibroblasts, and transformed lymphocytes. Here we present a new screening technique using lymphocytes to identify OXPHOS dysfunction and initially avoid an invasive diagnostic procedure. Lymphocytes represent an easily obtainable source of tissue that presents advantages over the use of fibroblasts or lymphoblast cell lines. The time delay in culturing skin fibroblasts and the interactions between cell transformation and mitochondrial activity are avoided in this methodology. The method requires a small amount of blood (<5 mL); can be completed in a few hours, and allows for repeated measurements. Our assay has been adapted from published methods utilizing cultured fibroblasts and transformed lymphocytes, and our data suggest that measurement of ATP synthesis in lymphocytes is an effective screening tool for diagnosing OXPHOS disorders. This method may also provide an objective tool for monitoring response to treatment and evaluating progression of disease.

Adult↗
PubMed2003

Autosomal dominant macular dystrophy in a large Canadian family.

BACKGROUND: We studied a large Canadian family (178 total family members) spanning seven generations with autosomal dominant macular dystrophy. We performed a study to identify the gene mutation responsible for the disease in the family. METHODS: Participating family members were evaluated clinically. Genetic linkage, genotyping, mutation screening and an extensive genealogic investigation were performed. RESULTS: The common clinical findings in affected family members included progressive early- to mid-onset visual loss and extensive areas of central chorioretinal atrophy. Two-point linkage analysis indicated linkage to chromosome 6p. Direct DNA sequencing showed a C/T transition in codon 172 of the retinal degeneration slow (RDS) gene creating an amino acid change to Arg172Trp. Haplotype analysis of affected family members using microsatellite markers distributed around the RDS gene locus revealed that the markers were not conserved when compared to members of British families with the Arg172Trp mutation. Genealogic studies indicated the family immigrated to Canada from Ireland in 1843. INTERPRETATION: A newly identified large family with autosomal dominant macular dystrophy is described. The phenotypic appearance of the fundus is similar to that of previously described patients with an Arg172Trp mutation in the RDS gene. Haplotype analysis of markers spanning the disease locus identified a new founder for this mutation. The identification of the disease-causing gene in this family allows for better genetic counselling for patients with this condition and provides a basis to distinguish clinically similar types of macular dystrophy based on the clinical phenotype.

Adult↗
PubMed2003

Clinical diagnoses that overlap with choroideremia.

PURPOSE: To understand which clinical presentations suggest a diagnosis of choroideremia (CHM). METHODS: Retrospective chart review. Included were patients for whom a clinical diagnosis of CHM was suggested, but either protein analysis or direct sequencing of the CHM gene could not confirm the diagnosis. Clinical presentation, family history and fundus photographs were reviewed. RESULTS: We analyzed protein and DNA samples from members of more than 100 families in which at least 1 member had a clinical diagnosis of CHM. For 26 of these families, the clinical diagnosis of CHM could not be confirmed by laboratory analysis. Relevant clinical information was requested from the referring ophthalmologists so that alternative diagnoses could be considered. Sufficient information was provided for 13 of the 26 families. Four patients were reclassified as having retinitis pigmentosa (RP) from the clinical phenotype; only two clearly had X-linked inheritance. One patient had a syndrome including macular dystrophy, hearing loss, developmental delay and cerebral palsy. One patient was reclassified as having congenital stationary night blindness on the basis of an electronegative electroretinogram and a normal fundus. One patient had hearing loss suggesting Usher syndrome. One patient had signs consistent with cone-rod dystrophy (CRD). Five patients could not be reclassified on the basis of the clinical presentation. CONCLUSION: RP, Usher syndrome and CRD are clinical phenotypes that may overlap with CHM. Clinical features that suggest CHM include severe chorioretinal atrophy with preservation of the macula, X-linked inheritance and retinal changes in a related female.

Adaptor Proteins, Signal Transducing↗
PubMed2003

A novel syndrome of congenital lid and punctal anomalies, corneal and chorioretinal dystrophy.

A 28-year old woman had an ocular syndrome consisting of congenital lid and punctal anomalies, and corneal and chorioretinal dystrophy without facial dysmorphism. These combined malformations of the ocular adnexae and both anterior and posterior ocular segments have not been previously described and appear to represent a novel syndrome. Direct sequencing of PAX6 and the DNA-binding domain of FOXC1 failed to detect a mutation.

Adult↗
PubMed2002

Mutational analysis of patients with the diagnosis of choroideremia.

All reported mutations in the choroideremia (CHM) gene result in the truncation or complete absence of Rab escort protein 1 (REP1). Molecular analysis was carried out on 57 families diagnosed with CHM. Confirmation of the clinical diagnosis is important as end-stage CHM may be clinically similar to the end stages of other retinal degenerative diseases such as RP. The primary means of confirming the diagnosis of CHM is to sequence all 15 exons. An alternative method involves detection of the REP1 protein, as described in MacDonald et al. [1998]. A monoclonal antibody to REP1 does not detect truncated REP1 by immunoblot analysis, presumably due to instability and subsequent degradation of the truncated protein. This analysis provides relatively fast confirmation of the diagnosis, however, protein samples are not always available and are susceptible to degradation, affecting the accurate interpretation of results. CHM gene mutations were found in 54 of 57 families studied. The majority of mutations (>42%) were transitions and transversions. Complete deletions of the CHM gene and deletion/insertion mutations each accounted for almost 4% of the total, while over 9% had large intragenic and other partial deletions. Almost 28% of the mutations were deletions of fewer than 5 base pairs (bp) and almost 13% were splice site mutations. Despite the fact that mutations are found throughout the gene with no common mutation for the disorder, identical mutations have been characterized in unrelated individuals. The majority of these mutations are C to T transitions, changing an arginine residue (CGA) to a stop codon (TGA). Four of the five CGA codons in the CHM gene are sites of recurring mutations.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Macular pigment and lutein supplementation in choroideremia.

Choroideremia is an incurable X-linked retinal degeneration caused by mutations in the gene encoding Rab escort protein-1. A group of clinically defined and genotyped patients were studied to determine: (1) the degree of rod and cone dysfunction and structural abnormality in the central retina and the level of macular pigment; and (2) the response of macular pigment and foveal vision to a 6 month trial of supplementation with oral lutein (at 20 mg per day). Rod and cone-mediated function was measured with dark-adapted static perimetry; in vivo retinal structure was determined with optical coherence tomography; and macular pigment optical density was measured with heterochromatic flicker photometry. In this cohort of patients (ages 15-65 years), both rod- and cone-mediated central function declined with age as did central retinal thickness. Macular pigment levels did not differ between patients and male control subjects. Supplementation of oral lutein in a subset of patients led to an increase in serum lutein and macular pigment levels; absolute foveal sensitivity did not change. It is concluded that macular pigment density can be augmented by oral intake of lutein in patients with choroideremia. There was no short-term change in the central vision of the patients on the supplement, but long-term influences of lutein supplementation on disease natural history warrant further study.

Adolescent↗