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PubMed1986

Choroideremia. A clinical and genetic study of 84 Finnish patients and 126 female carriers.

The aim of this work was to identify the choroideremia families in northern Finland, form an impression of the incidence of the disease in Finland, construct a picture of its clinical progression and gather new information on relevant genetic questions. A total of 111 choroideremia patients and 188 carriers were traced, members of four families from northern Finland and one from the Savo district. Ophthalmological confirmation was obtained for 84 choroideremia cases and 126 carriers. The largest of the families from northern Finland contained 80 cases of the disease and 146 carriers in eight generations among a total of more than 3000 descendants from one ancestral mother. The clinical picture for choroideremia proved to be more variable than could have been supposed from the literature, including cases of patients under 30 years of age who were already virtually blind and of patients of over 50 who were subjectively symptom-free. Only 7 out of 105 carriers could be shown anamnestically to have had subjective symptoms, but surprisingly, as many as 21 out of 52 carriers examined had changes in the visual field and 13 out of 40 examined showed deterioration in dark adaptation. One carrier was seen to undergo an obvious decline in dark adaptation during a three-year observation period. One indirect indication of the progression of fundus changes in choroideremia carriers was obtained from the fact that these changes, and also alterations in visual field and dark adaptation, were greater in the older carriers. A progression could also be detected by fundus photography in six instances, although the changes involved were fairly mild ones. Considerable variety was noted in the fundus findings for the choroideremia carriers, there being some 80-year-old subjects with quite minor changes and some 20-year-olds with obvious, extensive changes. Practical visual acuity remained normal throughout life in the majority of the carriers, however. Diagnosis within the known choroideremia families was fairly difficult, especially at the early stages in the survey, and even later on a few cases aged up to ten years produced diagnostic problems. Quite often diagnosis was easy, however, and choroideremic fundus changes were even identified in two boys aged 3 and 8 months. No other diseases could be shown to be associated with choroideremia, and the occurrence of dominantly inherited olivopontocerebellar atrophy alongside choroideremia in one branch of a family may be regarded as a coincidence.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗

PubMed1987

Multipoint linkage analysis of loci in the proximal long arm of the human X chromosome: application to mapping the choroideremia locus.

Choroideremia (McK30310), an X-linked retinal dystrophy, causes progressive night blindness, visual field constriction, and eventual central blindness in affected males by the third to fourth decade of life. The biochemical basis of the disease is unknown, and prenatal diagnosis is not available. Subregional localization of the choroideremia locus to Xq13-22 was accomplished initially by linkage to two restriction-fragment-length polymorphisms (RFLPs), DXYS1 (Xq13-q21.1) and DXS3 (Xq21.3-22). We have now extended our linkage analysis to 12 families using nine RFLP markers between Xp11.3 and Xq26. Recombination frequencies of 0%-4% were found between choroideremia and five markers (PGK, DXS3, DXYS12, DXS72, and DXYS1) located in Xq13-22. The families were also used to measure recombination frequencies between RFLP loci to provide parameters for the program LINKMAP. Multipoint analysis with LINKMAP provided overwhelming evidence for placing the choroideremia locus within the region bounded by DXS1 (Xq11-13) and DXS17 (Xq21.3-q22). At a finer level of resolution, multipoint analysis suggested that the choroideremia locus was proximal to DXS3 (384:1 odds) rather than distal to it. Data were insufficient, however, to distinguish between a gene order that puts choroideremia between DXS3 and DXYS1 and one that places choroideremia proximal to both RFLP loci. These results provide linkage mapping of choroideremia and RFLP loci in this region that will be of use for further genetic studies as well as for clinical applications in this and other human diseases.

Choroid↗

PubMed1985

Choroideremia is linked to the restriction fragment length polymorphism DXYS1 at XQ13-21.

Choroideremia (McK30310), an X-linked hereditary retinal dystrophy, causes night-blindness, progressive peripheral visual field loss, and, ultimately, central blindness in affected males. The location of choroideremia on the X chromosome is unknown. We have used restriction fragment length polymorphisms from the X chromosome to determine the regional localization of choroideremia by linkage analysis in families with this disease. One such polymorphic locus, DXYS1, located on the long arm (Xq) within bands q13-q21, shows no recombination with choroideremia at lod = 5.78. Therefore, with 90% probability, choroideremia maps within 9 centiMorgans (cM) of DXYS1. Another polymorphic locus, DXS11, located within Xq24-q26, also shows no recombination with choroideremia, although at a smaller lod score of 1.54 (90% probability limit theta less than 30 cM). This linkage with DXS11, a marker that is distal to DXYS1, suggests that the locus for choroideremia is also distal to DXYS1 and lies between these two markers in the region Xq13-q24. These results provide regional mapping for the disease that may be useful for prenatal diagnosis and, perhaps ultimately, for isolating the gene locus for choroideremia.

Choroid↗

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↗

PubMed1989

Choroideremia and deafness with stapes fixation: a contiguous gene deletion syndrome in Xq21.

The study of contiguous gene deletion syndromes by using reverse genetic techniques provides a powerful tool for precisely defining the map location of the genes involved. We have made use of individuals with overlapping deletions producing choroideremia as part of a complex phenotype, to define the boundaries on the X chromosome for this gene, as well as for X-linked mixed deafness with perilymphatic gusher (DFN3). Two patients with deletions and choroideremia are affected by an X-linked mixed conductive/sensorineural deafness; one patient, XL-62, was confirmed at surgery to have DFN3, while the other patient, XL-45, is suspected clinically to have the same disorder. A third choroideremia deletion patient, MBU, has normal hearing. Patient XL-62 has a cytogenetically detectable deletion that was measured to be 7.7% of the X chromosome by dual laser flow cytometry; the other patient, XL-45, has a cytogenetically undetectable deletion that measures only 3.3% of the X chromosome. We have produced a physical map of the X-chromosome region containing choroideremia and DFN3 by using routine Southern blotting, chromosome walking and jumping techniques, and long-range restriction mapping to generate and link anonymous DNA sequences in this region. DXS232 and DXS233 are located within 450 kb of each other on the same SfiI and MluI fragments and share partial SalI fragments of 750 and greater than 1,000 kb but are separated by at least one SalI site. In addition, DXS232, which lies outside the MBU deletion, detects the proximal breakpoint of this deletion. We have isolated two new anonymous DNA sequences by chromosome jumping from DXS233; one of these detects a new SfiI fragment distal to DXS233 in the direction of the choroideremia gene, while the other jump clone is proximal to DXS233 and detects a new polymorphism. These data refine the map around the loci for choroideremia and for mixed deafness with stapes fixation and will provide points from which to isolate candidate gene sequences for these disorders.

Adolescent↗

PubMed1985

Mapping X-linked ophthalmic diseases. Provisional assignment of the locus for choroideremia to Xq13-q24.

Choroideremia (McK 30310), an X-linked hereditary retinal dystrophy, causes nyctalopia, progressive visual field loss, and ultimately central blindness in affected males in early adulthood. We have used restriction fragment length polymorphisms from the X-chromosome to localize the region of the mutation for choroideremia in three families with this disorder. One polymorphic marker, DXYS1, located within Xq13-q21, shows no recombination with choroideremia at a LOD score of 5.78. Thus choroideremia maps within 9 centiMorgans of DXYS1 at 90% probability. Another marker, DXS11, located at Xq24-q26, shows no recombination with choroideremia but at a smaller LOD score of 1.54. These results suggest that the locus for choroideremia is distal to DXYS1 and between the two markers in the region Xq13-q24. This information may be useful for antenatal diagnosis, isolation of the mutant gene, and development of a rational therapy for the disorder.

Adult↗

PubMed1990

Choroideremia associated with an X-autosomal translocation.

A patient with mild choroideremia has been shown to carry a balanced translocation between chromosome X and 13-46,X,t(X;13)(q21.2;p12). Loci (DXY21, DX232, DX233) shown to map to this region on the X chromosome and in some cases to be deleted in other patients with choroideremia are intact in the DNA from this patient. To our knowledge this is the first report of a translocation associated with choroideremia. One of the translocation chromosomes, derivative 13, free of the derivative X and normal X, has been isolated in a somatic cell hybrid. Because of the clinical association of the eye findings with chromosome interchange, we suggest that the breakpoint on the X is at or near the choroideremia locus. Further analysis of this translocation may be useful in cloning the choroideremia gene.

Adult↗

PubMed1996

Choroideremia with leukoencephalopathy and arylsulfatase A pseudodeficiency.

A 33-year-old male patient was admitted to our hospital because of progressive gait disturbance and involuntary movement of the neck. He showed choroideremia, distal motor neuropathy, and leukoencephalopathy on T2-weighted brain magnetic resonance imaging (MRI). Choroideremia is a rare X-linked, progressive, degenerative disease of retina and choroid. There have been some reports of choroideremia patients with neurological complications. Recent studies have assigned its genetic locus to a small segment of Xq21.3 and it encodes a protein that resembles component A of rat Rab geranyl-geranyl transferase, a protein essential for cell function. This patient did not have the reported genetic abnormalities for choroideremia. Known disorders causing leukoencephalopathy were not detected except for a partial deficiency of arylsulfatase A (17.3% of normal controls in lymphocytes and 13.7% in fibroblasts). Deficiency of arylsulfatase A activity occurs in the late infantile, juvenile, and adult forms of metachromatic leukodystrophy (MLD) which is also an inherited disorder of myelin metabolism, but because of its unstability, it occurs in normal individuals and in patients with other neurological diseases. Consequently, we suspect that this patient had partial deficiency of arylsulfatase A and choroideremia as predisposing factors for white matter degeneration.

Adult↗

PubMed1998

Intraocular light scatter in patients with choroideremia.

OBJECTIVE: This study aimed to evaluate the extent of intraocular light scatter in patients with choroideremia. DESIGN: Prospective case-control study. PARTICIPANTS: Twelve male patients with choroideremia who had predominantly minimal or no posterior subcapsular cataract (PSC) lens opacities and visual acuities of 20/40 or better and 30 age-similar control subjects with normal vision and no lens opacities were studied. INTERVENTION: Intraocular light scatter was measured using a van den Berg Straylightmeter. MAIN OUTCOME MEASURES: Visual acuities, letter contrast sensitivities, Goldmann visual fields using a II4e target, and straylight parameters were obtained for each patient. Lenses were assessed by slit-lamp biomicroscopy to determine whether there were PSC opacities. The degree of retinal pigment epithelial and choroidal degenerative changes was evaluated from color fundus photographs. RESULTS: Three of the patients with choroideremia who had clinically apparent PSC lens opacities showed an increase in intraocular light scatter. More notable was the fact that seven of the remaining nine patients who did not have any clinically apparent changes in the lens also had a considerable increase in the intraocular light scatter as compared to the control subjects. The relative elevations of the log straylight parameters of the patients with choroideremia, as compared to age-similar control subjects, were correlated significantly with their log visual field areas (r = -0.69, P < 0.05). CONCLUSIONS: Intraocular light scatter may be increased in patients with choroideremia, even in the absence of clinically observable PSC opacities. It is hypothesized that the increase in light scatter may be caused by changes in the posterior subcapsular region of the lens before the formation of frank PSC cataracts. The increased straylight could, at least in part, account for the disability glare reported by these patients.

Adult↗

PubMed1992

Isolation of a candidate gene for choroideremia.

Choroideremia is an X chromosome-linked retinal dystrophy of unknown pathogenesis. We have isolated cDNAs from a human retinal library with a genomic probe located at the X chromosomal breakpoint in a female with choroideremia and an X;13 translocation. This cDNA spans the breakpoint in the X;13 translocation female and is deleted in males who have choroideremia as part of a complex phenotype including mental retardation and deafness. However, this cDNA detects no alterations in the DNA of 34 males with isolated choroideremia. Nonetheless, the cDNA does detect reduced or absent levels of mRNA in three-quarters of male patients with an apparently intact gene. These data support the hypothesis that this cDNA represents the gene in which mutations cause choroideremia.

Amino Acid Sequence↗

PubMed1995

Deficient geranylgeranylation of Ram/Rab27 in choroideremia.

Choroideremia, an X-linked form of retinal degeneration, results from defects in the Rab escort protein-1 (REP-1) gene. REP-1 and REP-2 assist in the attachment of geranylgeranyl groups to Rab GTPases, a modification essential for their action as molecular switches regulating intracellular vesicular transport. If Rabs that depend preferentially on REP-1 for prenylation exist, they will accumulate unprenylated in choroideremia cells. Using recombinant Rab geranylgeranyl transferase and REPs to label unprenylated cytosolic proteins, we identified one unprenylated protein in choroideremia lymphoblasts that was prenylated in vitro more efficiently by REP-1 than by REP-2. This protein was purified and identified as Ram (renamed Rab27), a previously cloned Rab of unknown function. Immunohistochemistry of rat retina showed that Ram/Rab27 is expressed in the pigment epithelium and choriocapillaris, the two retinal cell layers that degenerate earliest in choroideremia. These results raise the possibility that the retinal degeneration in choroideremia results from the deficient geranylgeranylation of Ram/Rab27 or a closely related protein.

Adaptor Proteins, Signal Transducing↗

PubMed2004

Clinical features of Japanese families with a 402delT or a 555-556delAG mutation in choroideremia gene.

PURPOSE: To characterize the clinical features of two Japanese families with choroideremia associated with a 402delT and a 555-556delAG mutation in the choroideremia gene (CHM). METHODS: Four affected members and one obligate carrier from two Japanese families with choroideremia were studied. To detect mutations of the CHM gene, the products of polymerase chain reaction were directly sequenced in both directions. The ophthalmologic examination included best-corrected visual acuity, slit-lamp examination, fundus examination, kinetic perimetry, electroretinography, and fluorescein angiography. RESULTS: A 402delT and a 555-556delAG mutation were found in two Japanese families with choroideremia. All affected members had night-blindness, progressive constriction of the visual field, chorioretinal atrophy, and mottled appearance of the retinal pigment epithelium. The obligate carrier had mild patchy areas of retinal pigment epithelial atrophy with no visual symptoms. CONCLUSION: The authors found a 402delT and a 555-556delAG mutation in the CHM gene, one of which (402delT) is a novel mutation. They conclude that these mutations cause choroideremia in Japanese families.

Adaptor Proteins, Signal Transducing↗

PubMed1986

Choroideremia: further evidence for assignment of the locus to Xq13-Xq21.

Choroideremia is an X-linked hereditary retinal dystrophy leading to blindness in early adulthood. RFLP analyses in three Danish families were consistent with close linkage between choroideremia and the locus DXYS1, located at Xq13-Xq21. Measurable linkage was found between choroideremia and DXS17, at Xq22. Furthermore, choroideremia was diagnosed in a boy with an interstitial deletion at Xq13-Xq21, strongly suggesting the assignment of the locus for choroideremia to this region of the X chromosome. The deletion also covered DXYS1, but did not include DXS17.

Chromosome Mapping↗

PubMed1990

DXS165 detects a translocation breakpoint in a woman with choroideremia and a de novo X; 13 translocation.

The search for the gene for choroideremia (MIM 30310), a rare retinal dystrophy, has been of great interest due to the existence of several choroideremia patients with well-defined structural chromosome aberrations, thus providing the basis for a reverse genetics approach to the isolation of this disease gene. This report details our molecular studies of a woman with choroideremia and a de novo X; 13 translocation. Pulsed-field gel electrophoresis using a contour-clamped homogeneous electric field apparatus has allowed detection of the translocation breakpoint with the anonymous DNA marker p1bD5 (DXS165) and the mapping of this probe to within 120 kb of the breakpoint. In addition, we have used this probe to isolate a clone (pCH4) from a 100-kb jumping library which has crossed a rare-cutting restriction site (XhoI) between DXS165 and the choroideremia gene and detects the translocation breakpoint using this enzyme. Although DXS165 lies within 120 kb of the breakpoint and Cremers et al. (1987, Clin. Genet. 32: 421-423; 1989, PNAS 86: 7510-7514) have detected deletions of DXS165 in 3 of 30 choroideremia probands, we have detected no deletions of this marker or of pCH4 in 42 unrelated probands with this retinal disease.

Animals↗

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↗

PubMed1990

Derivation of clones from the choroideremia locus by preparative field inversion gel electrophoresis.

By making use of preparative field inversion gel electrophoresis, we have constructed a lambda ZAP library that is highly enriched for sequences from the choroideremia locus. In vivo excision of pBluescript SK(-) constructs from lambda ZAP obviates the subcloning of DNA inserts and allows for rapid processing of several hundred recombinants. From a 625 kb Sfil fragment we isolated 7 clones that were physically mapped using microdeletions associated with the disease. One of these clones is located within, or just telomeric to, the choroideremia gene and detects two restriction fragment length polymorphisms (RFLPs). Another clone detects a RFLP which maps centromeric to the disease locus. Together these probes should improve the reliability of linkage analysis in choroideremia families and should pave the way for the isolation of the choroideremia gene.

Animals↗

PubMed2005

[Quality of life in patients suffering from choroideremia].

PURPOSE: To direct attention on every-day problems in choroideremia, which are not a barrier in patients occupation. MATERIAL AND METHODS: Two cases of patients with choroideremia which was diagnosed when they were 30 and 54 are described. In spite of widespread visual field changes patients with good visual acuity did not have to change their lifestyles or their jobs (miner and mechanic). Visual acuity, visual field, mesoptometry, adaptometry, electroretinography, electrooculography were done. The mother of the younger patient was also examined. Her fundus of the eye showed typical changes for carriers. In the older patient's family among 41 family members 7 men were affected in 3 generations. Follow-up was 6 years. RESULTS: In ERG rod activity was very low or abolished and cone activity was reduced, more in older patient. In the younger patient visual acuity and mesoptometry were normal, rod adaptation was very low. The patient was able to work as a miner due to good mesopic vision. In follow-up no significant progression of the disease was observed. The older patient had previously been treated for retinitis pigmentosa for a few years. Diagnosis of choroideremia was made when visual acuity of the patient declined. It was impossible to perform mesoptometry and adaptometry because of advanced night blindness. In the dark room the patient found it very difficult to move. In follow-up lowering of the visual acuity, progression of visual field as well as electroretinographic changes occurred. CONCLUSIONS: Patients with choroideremia may be professionally engaged despite of every-day problems connected with widespread scotomas in visual field and nyctalopia. They should not become pensioners too early. The disease progression is faster in older than in younger patients.

Adult↗

PubMed1987

Isolation of anonymous DNA sequences from within a submicroscopic X chromosomal deletion in a patient with choroideremia, deafness, and mental retardation.

Choroideremia, an X-chromosome linked retinal dystrophy of unknown pathogenesis, causes progressive nightblindness and eventual central blindness in affected males by the third to fourth decade of life. Choroideremia has been mapped to Xq13-21 by tight linkage to restriction fragment length polymorphism loci. We have recently identified two families in which choroideremia is inherited with mental retardation and deafness. In family XL-62, an interstitial deletion in Xq21 is visible by cytogenetic analysis and two linked anonymous DNA markers, DXYS1 and DXS72, are deleted. In the second family, XL-45, an interstitial deletion was suspected on phenotypic grounds but could not be confirmed by high-resolution cytogenetic analysis. We used phenol-enhanced reassociation of 48,XXXX DNA in competition with excess XL-45 DNA to generate a library of cloned DNA enriched for sequences that might be deleted in XL-45. Two of the first 83 sequences characterized from the library were found to be deleted in probands from family XL-45 as well as from family XL-62. Isolation of these sequences proves that XL-45 does contain a submicroscopic deletion and provides a starting point for identifying overlapping genomic sequences that span the XL-45 deletion. Each overlapping sequence will be studied to identify exons from the choroideremia locus.

Chromosome Mapping↗