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Biomedical subjects

I H Maumenee

Publications and source records attributed to I H Maumenee.

At least 55 records · Page 3Linked to original sources
PubMed1993

Identification of novel rhodopsin mutations responsible for retinitis pigmentosa: implications for the structure and function of rhodopsin.

Ten rhodopsin mutations have been found in a screen of 282 subjects with retinitis pigmentosa (RP), 76 subjects with Leber congenital amaurosis, and 3 subjects with congenital stationary night blindness. Eight of these mutations (gly51-to-ala, val104-to-ile, gly106-to-arg, arg135-to-gly, cys140-to-ser, gly188-to-glu, val209-to-met, and his211-to-arg) produce amino acid substitutions, one (gln64-to-ter) introduces a stop codon, and one changes a guanosine in the intron 4 consensus splice donor sequence to thymidine. Cosegregation of RP with gln64-to-ter, gly106-to-arg, arg135-to-gly, cys140-to-ser, gly188-to-glu, his211-to-arg, and the splice site guanosine-to-thymidine indicates that these mutations are likely to cause retinal disease. Val104-to-ile does not cosegregate and is therefore unlikely to be related to retinal disease. The relevance of gly51-to-ala and val209-to-met remains to be determined. The finding of gln64-to-ter in a family with autosomal dominant RP is in contrast to a recent report of a recessive disease phenotype associated with the rhodopsin mutation glu249-to-ter. In the present screen, all of the mutations that cosegregate with retinal disease were found among patients with RP. The mutations described here bring to 35 the total number of amino acid substitutions identified thus far in rhodopsin that are associated with RP. The distribution of the substitutions along the polypeptide chain is significantly nonrandom: 63% of the substitutions involve those 19% of amino acids that are identical among vertebrate visual pigments sequenced to date.

Alleles↗
PubMed1992

Ocular findings in Cockayne syndrome.

The ocular findings in eight patients with Cockayne syndrome included enophthalmos, hyperopia, poor pupillary dilation, and retinal dystrophy in all patients. Four patients had strabismus. Two patients had cataracts. Three patients had nystagmus. Visual acuity was relatively well preserved in six patients, including a 25-year-old man with a visual acuity of 20/60 in each eye despite advanced retinal pigmentary changes. Failure of DNA and RNA synthesis to recover after ultraviolet light exposure as well as selective loss of repair of transcriptionally active DNA may account for the ocular abnormality in this progeric syndrome.

Adult↗
PubMed1992

Ocular histopathologic characteristics of cobalamin C type vitamin B12 defect with methylmalonic aciduria and homocystinuria.

The eyes of a 22-month-old girl with the cobalamin C complementation type of combined methylmalonic aciduria and homocystinuria were studied with light and electron microscopy. We observed vacuolization of the iris pigment epithelium, loss of photoreceptors in the central 3.3 mm of the macula, partial loss of the nerve fiber and ganglion cell layers between the fovea and optic disk, and partial optic atrophy. The sclera in the posterior pole was thickened with deposition of mucopolysaccharide. Electron microscopy showed inclusions containing fine granular material in conjunctival fibrocytes; corneal epithelium, keratocytes, and endothelial cells; iris pigment epithelium; ganglion cells; retinal pigment epithelium; and choroid and scleral fibrocytes. Enlarged mitochondria and clear vacuoles distended the corneal endothelial cells. We found evidence of possible lysosomal dysfunction and mucopolysaccharide storage, as well as a clinicopathologic correlation of the macular degeneration in this disease.

Eye↗
PubMed1992

Mitochondrial DNA mutation and heteroplasmy in type I Leber hereditary optic neuropathy.

Leber hereditary optic neuropathy (LHON) is a maternally inherited disorder characterized by bilateral acute or subacute loss of central vision, primarily in young males. A G----A single base mutation at 11778nt of the mitochondrial genome which eliminates a SfaNI restriction site [Wallace et al., 1988; Holt et al., 1989; Hotta et al., 1989; Singh et al., 1989; Vilkki et al., 1989; Yoneda et al., 1989; Stone et al., 1990; Lott et al., 1990.] has been found in more than 60% of the families with LHON studied. We studied 25 persons from 4 families with LHON using SfaNI and Mae III digestion of a 201 base pair polymerase chain reaction (PCR) product encompassing the 11778nt mutation. The loss of the SfaNI site and the acquisition of a Mae III site at 11778nt were identified in all maternal relatives of the LHON families studied. The mutation was heteroplasmic in all affected individuals, female carriers, and males at-risk. The heteroplasmy of mitochondrial DNA (mtDNA) was also identified by direct DNA sequencing of PCR amplified by direct DNA sequencing of PCR amplified mtDNA digested by SfaNI or Mae III. It appears that the proportion of the mutant mtDNA correlates with the severity of the disease.

Adenine↗
PubMed1992

Clinical, biochemical, and neuropsychiatric evaluation of a patient with a contiguous gene syndrome due to a microdeletion Xp11.3 including the Norrie disease locus and monoamine oxidase (MAOA and MAOB) genes.

Norrie disease is a rare X-linked recessive disorder characterized by blindness from infancy. The gene for Norrie disease has been localized to Xp11.3. More recently, the genes for monoamine oxidase (MAOA, MAOB) have been mapped to the same region. This study evaluates the clinical, biochemical, and neuropsychiatric data in an affected male and 2 obligate heterozygote females from a single family with a submicroscopic deletion involving Norrie disease and MAO genes. The propositus was a profoundly retarded, blind male; he also had neurologic abnormalities including myoclonus and stereotopy-habit disorder. Both obligate carrier females had a normal IQ. The propositus' mother met diagnostic criteria for "chronic hypomania and schizotypal features." The propositus' MAO activity was undetectable and the female heterozygotes had reduced levels comparable to patients receiving MAO inhibiting antidepressants. MAO substrate and metabolite abnormalities were found in the propositus' plasma and CSF. This study indicates that subtle biochemical and possibly neuropsychiatric abnormalities may be detected in some heterozygotes with the microdeletion in Xp11.3 due to loss of the gene product for the MAO genes; this deletion can also explain some of the complex phenotype of this contiguous gene syndrome in the propositus.

Adolescent↗
PubMed1992

Peters' anomaly and associated congenital malformations.

We reviewed the clinical findings in 29 patients with Peters' anomaly. There was developmental delay in 15 patients, congenital heart disease in eight patients, external ear abnormalities in five patients, structural defects of the central nervous system in four patients, genitourinary malformations in four patients, cleft lip/palate in three patients, hearing loss in three patients, spinal defects in two patients, and single cases of other less common defects. One patient had fetal alcohol syndrome; one, Pfeiffer's syndrome; and one, short stature, ulnar hypoplasia, and joint laxity. Colobomatous microphthalmia was present in seven patients, and persistent hyperplastic primary vitreous in three patients. Ten patients developed glaucoma, and three had retinal detachment unrelated to ocular surgery. Peters' anomaly may be due to a developmental field defect, or the complex ocular and systemic malformations may be the result of a contiguous gene syndrome or of a defective homeotic gene controlling the development of the eye and other body structures.

Abnormalities, Multiple↗
PubMed1992

The natural history of Leber's congenital amaurosis. Age-related findings in 35 patients.

The authors studied 35 patients with Leber's congenital amaurosis and assessed visual acuity, fundus appearance, and systemic findings. The patients were arbitrarily divided into five age groups. Visual acuities were comparable at all ages. Of 22 patients seen for follow-up examinations (mean length of follow-up, 5 years), vision worsened slightly in only 4 patients (3 with macular coloboma-like lesions and 1 with keratoconus). Fifty percent of retinal examinations in patients younger than 1 year of age were normal. With increasing age, retinal pigmentary changes became evident. All but four patients seen on more than one occasion developed progressive retinal/retinal pigment epithelium changes. Cataracts (5 patients) and keratoconus (3 patients) were present only in older patients (9 to 33 years of age). In Leber's congenital amaurosis, which probably comprises a number of genetically heterogenous conditions, visual acuity remains stable despite progressive retinal pigmentary changes. The subgroup of patients with macular colobomas, however, may develop progressive decrease in vision. Cataracts and keratoconus are additional factors contributing to visual impairment in older patients.

Adolescent↗
PubMed1992

Molecular genetic analysis in autosomal dominant keratoconus.

Members in three generations of a family whose propositus had keratoconus were examined by biomicroscopy, with a corneoscope and a computer-assisted videophoto-keratoscope. Keratoconus was detected in eight of 15 family members with vertical transmission consistent with autosomal dominant inheritance. Affected individuals displayed variable topographic features. Abortive "nipple-type" cones were identified in some individuals in successive generations using the computer-assisted videophotokeratoscope and more advanced nipple-type cones detected on biomicroscopy of other family members. We selected a COL6A1 cDNA (the gene encoding the alpha 1 chain of type VI collagen) as a "candidate gene" to determine cosegregation with the disease locus. Linkage analysis excluded a gene locus for keratoconus on the most telomeric region of chromosome 21 in this family.

Adult↗
PubMed1991

Rhodopsin mutations in autosomal dominant retinitis pigmentosa.

DNA samples from 161 unrelated patients with autosomal dominant retinitis pigmentosa were screened for point mutations in the rhodopsin gene by using the polymerase chain reaction and denaturing gradient gel electrophoresis. Thirty-nine patients were found to carry 1 of 13 different point mutations at 12 amino acid positions. The presence or absence of the mutations correlated with the presence or absence of retinitis pigmentosa in 174 out of 179 individuals tested in 17 families. The mutations were absent from 118 control subjects with normal vision.

Base Sequence↗
PubMed1991

Value of combined phenotypic markers in identifying inheritance of familial adenomatous polyposis.

Familial adenomatous polyposis is an autosomal dominant disease characterised by the development of hundreds of colorectal adenomas in young adults. Occult radio-opaque jaw lesions and pigmented ocular fundus lesions (formerly called congenital hypertrophy of the retinal pigment epithelium) are extraintestinal phenotypic markers for this disorder. We evaluated the usefulness of the combination of these markers for identifying patients who have inherited familial adenomatous polyposis. Forty three affected patients and 12 unaffected first degree relatives from 24 families with familial adenomatous polyposis, including four families without extraintestinal manifestations, were examined for both phenotypic markers. Thirty three of the 43 patients (77%) with familial adenomatous polyposis were positive for both markers, including patients from two families without extraintestinal manifestations. By contrast, only one of 12 (8%) unaffected first degree relatives over 35 years of age had both markers. The sensitivity of the combination of these markers in identifying patients who inherited familial adenomatous polyposis was 77%, the specificity 92%, the predictive value of a positive test 97%, the predictive value of a negative test 52%, and the efficacy 80%. The combined markers had improved efficacy over either marker alone (70% for occult radio-opaque jaw lesions and 67% for pigmented ocular fundus lesions). We conclude that the presence of both occult radio-opaque jaw lesions and pigmented ocular fundus lesions in a person at risk indicates a high probability of inheritance and expression of familial adenomatous polyposis.

Adenomatous Polyposis Coli↗
PubMed1991

Glycosaminoglycan degradation by cultured retinal pigment epithelium from patients with retinitis pigmentosa.

Patients with certain systemic deficiencies in the degradation of glycosaminoglycans (GAGs) often suffer from a retinal degeneration similar to that seen in retinitis pigmentosa. This applies to mucopolysaccharidosis (MPS) types I, II, and III, but not to type VI. The retinal pigment epithelium (RPE) is thought to contribute significantly to the synthesis and degradation of proteoglycans in the interphotoreceptor matrix. This raises the possibility that a defect in the synthesis or degradation of GAGs by the RPE may be related to some forms of retinal degeneration. In the present work, RPE from normal and RP donors was investigated for the capacity to correct deficiencies in GAG degradation by cultured skin fibroblasts from patients with different forms of MPS. A cross-correction technique was used in which abnormal increases in the incorporation of 35S-sulfate into GAGs by MPS fibroblasts was measured in the absence or presence of RPE cultures. RPE from normal donors corrected the defects in GAG degradation of fibroblasts from patients with MPS I, II, and III, but not MPS VI. The RPE from four donors with retinitis pigmentosa (one autosomal dominant, one sex-linked, and two isolated cases) and one donor with an unclassified isolated retinal degeneration demonstrated the same capacities to correct the MPS deficiencies as did normal RPE. Therefore, although retinitis pigmentosa is a heterogeneous disorder with several possible etiologies, no evidence was found in these five patients for a defect in GAG degradation that resembles the deficiencies of MPS patients.

Adult↗
PubMed1990

A clinicopathologic study of the eyes in familial adenomatous polyposis with extracolonic manifestations (Gardner's syndrome).

The eyes of a 51-year-old woman with familial adenomatous polyposis and extracolonic manifestations (Gardner's syndrome) were obtained postmortem and studied by light microscopy and by transmission and scanning electron microscopy. We found a generalized abnormality in melanogenesis of the retinal pigment epithelium and at least three types of pigmented lesions. The histologic findings in one type of lesion were consistent with congenital hypertrophy of the retinal pigment epithelium or benign pigmented nevus of the retinal pigment epithelium. The other two types of lesion were most consistent with hamartomatous malformations of the retinal pigment epithelium featuring cellular hypertrophy, hyperplasia, and rarely retinal invasion and formation of a minute mushroom-shaped tumor. These histopathologic findings indicate a generalized effect of the familial adenomatous polyposis gene on the retinal pigment epithelium. This oncogene, which is responsible for tumor formation in the gastrointestinal tract, soft tissues, bone, and other locations in patients with familial adenomatous polyposis, also leads to a generalized defect in melanogenesis and focal lesions of the retinal pigment epithelium.

Adenocarcinoma↗
PubMed1990

Congenital hypertrophy of the retinal pigment epithelium predicts colorectal polyposis in Gardner's syndrome.

We studied prospectively the utility of congenital hypertrophy of the retinal pigment epithelium as a predictor of colonic polyposis in offspring of patients with familial adenomatous polyposis with extracolonic manifestations (Gardner's syndrome). After they underwent initial indirect ophthalmoscopy, we followed up 34 individuals at 50% genetic risk for familial adenomatous polyposis with extracolonic manifestations due to an affected parent. All 34 obtained their first colorectal endoscopic examination during a follow-up period of up to 4 years. The 16 individuals who did not have congenital hypertrophy of the retinal pigment epithelium (aged 13 to 40 years; mean, 25 years) remained polyp free, while 14 of 18 individuals with congenital hypertrophy of the retinal pigment epithelium (aged 9 to 30 years; mean, 18 years) were found to have colorectal adenomatous polyposis. Our findings indicate that the presence of multiple patches of congenital hypertrophy of the retinal pigment epithelium in children and young adults at risk for familial adenomatous polyposis with extracolonic manifestations is a clinically useful predictor of colorectal polyposis.

Adenomatous Polyposis Coli↗
PubMed1990

Microphthalmos in the presumed homozygous offspring of a first cousin marriage and linkage analysis of a locus in a family with autosomal dominant cerulean congenital cataracts.

A family with autosomal dominant congenital cataracts was studied to determine clinical variability. A total of 159 relatives was ascertained; 17 affected and 19 normal individuals were evaluated and their blood sampled for inclusion in the linkage analysis. The disease was compatible with normal to mildly decreased visual acuity until adult life in all affected except the product of a consanguineous marriage of affected first cousins who was born with bilateral microphthalmos and dense congenital cataracts, attributed to homozygosity of the cataract gene. There were no extraocular abnormalities; the patient was of normal intelligence. Twenty-three markers were typed, 18 of which were informative. Linkage could be excluded for all 18 markers at short distances.

Cataract↗