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PubMed2006

Microphthalmia and brain atrophy: a novel neurodegenerative disease.

OBJECTIVE: To delineate the features of a novel neurodegenerative disease. METHODS: We report three children of three related families with congenital microphthalmia and blindness, and progressive spasticity, microcephaly, seizures, and profound mental retardation. RESULTS: A magnetic resonance imaging scan was normal at birth. However, follow-up studies showed progressive atrophy involving the cerebral white matter and cortex, cerebellum, brainstem, and corpus callosum. The white matter changes extended into the subcortical region leaving only small islands of remaining cortical tissue. Known metabolic conditions involving white matter degeneration were excluded. INTERPRETATION: We propose this to be a novel autosomal recessive neurodegenerative disorder to be coined MOBA (microphthalmia brain atrophy) disease.

Atrophy↗
PubMed1987

Extraocular muscles in the microphthalmic rat.

The extraocular muscles in a mutant microphthalmic strain of rat were studied. The eyeball of this strain of rat is reduced to about a third in diameter of that of the normal rat. Nevertheless, in the orbit of the mutant rat, every one of the extraocular muscles was identified; their origins and courses were the same as in the normal rat, but differences existed in the insertions. These insertions could be classified into three groups: Group A (retractor bulbi): like normal insertion into the eyeball. Group B (superior rectus and superior oblique): attachment of tendonlike insertions to each other; these muscles come from opposite directions and form a loop. Group C (lateral, medial, and inferior rectus and inferior oblique): insertion into connective tissue surrounding the reduced eyeball. The volume of each muscle of the mutant rat was smaller than that of the normal rat; moreover, significant differences existed in the degree of reduction in the volume of each muscle group classified according to the change of insertion. In the group A muscle the volume was only 33% of the normal volume, whereas group B was 74% and group C was about half of normal.

Animals↗
PubMed2003

High exogenous homocysteine modifies eye development in early chick embryos.

BACKGROUND: Homocysteine is a nonessential aminoacid whose increase is related to the appearance of neural tube defects in humans. In chick embryos, high levels of homocysteine produce neural tube defects and alteration of neural crest cell migration. METHODS: In our study, 8 microl of L-homocysteine thiolatone (20 micromol) was added to chick embryos of Stages 3-8/10 (Hamburger and Hamilton, 1951), (1238 hr of incubation). Three days later, 50 embryos, externally normal or carrying isolated spinal neural tube defects, were sectioned and stained by hematoxilin-eosin or anti-fibrillin-1 antibody. RESULTS: The eye showed alterations of the optic cup as microphthalmia, or lens dislocation. In both cases, the incidence of alterations diminished with the age of the homocysteine-increased embryos. Optic cup modifications are probably associated with central nervous system alterations, because most of the affected embryos exhibited isolated spinal neural tube defects and had altered neural crest cells. We have shown for the first time that high exogenous homocysteine during early development could produce a caudally-displaced lens axis before the zonule is formed. Fibrillin-1 is the main component of elastic microfibrils, and in the adult human it is seen as a protein particularly susceptible to homocysteine attack. CONCLUSIONS: Antibody staining against fibrillin-1 showed no evident morphological differences in distribution between experimental and control embryos in the lens, suggesting that fibrillin-1 was not the cause, and malformations may be attributed to other mechanisms.

Abnormalities, Drug-Induced↗
PubMed2003

Exposure-disease continuum for 2-chloro-2'-deoxyadenosine, a prototype ocular teratogen. 3. Intervention with PK11195.

BACKGROUND: Treatment of pregnant mice with 2-chloro-2'-deoxyadenosine (2CdA) on Day 8 of gestation induces microphthalmia through a mechanism linked to the p53 tumor suppressor pathway. The present study defines the response of Day 8 mouse embryos through time with respect to pharmacologic intervention with PK11195, a ligand of the mitochondrial peripheral benzodiazepine receptor (Bzrp). METHODS: Pregnant CD-1 mice dosed with 2CdA with or without PK11195 on gestation Day 8 provided fetuses for teratologic evaluation on Day 14 and Day 17; HPLC measured pyridine nucleotides (NADH/NAD+) at 1.5 hr, RT-PCR measured mitochondrial 16S rRNA abundance at 3.0 hr, and p53 protein induction was assessed with immunostaining at 4.5 hr postexposure. RESULTS: The mean incidences of malformed fetuses were significantly higher in the 7.5 mg/kg 2CdA treatment group (50.2% malformed) vs. the 2CdA + 4.0 mg/kg PK11195 co-treatment group (4.4% malformed). Malformed fetuses displayed a range of ocular defects that included microphthalmia and keratolenticular dysgenesis (Peters anomaly). No malformations were observed in the control or PK11195 alone groups. PK11195 also protected litters from increased resorption rates and fetal weight reduction. It did not rescue early effects on NADH balance (1.5 hr) or 16S rRNA expression (3.0 hr); however, the p53 response (4.5 hr) was downgraded in 2CdA + PK11195 embryos vs. 2CdA alone. By delaying the administration of PK11195 in 1.5 hr intervals it was determined that the window for protection closed between 4.5 to 6.0 hr after 2CdA. CONCLUSIONS: The capacity of PK11195 to suppress the pathogenesis of microphthalmia implies a critical role for mitochondrial peripheral benzodiazepine receptors in the p53-dependent mode of action of 2CdA on ocular development.

Animals↗
PubMed2006

Descriptive epidemiology of anophthalmia and microphthalmia, Hawaii, 1986-2001.

BACKGROUND: Population-based epidemiologic data on anophthalmia and microphthalmia in the United States are limited and have come mainly from only a few states. The intent of this study was to report on the epidemiology of these eye defects. METHODS: Cases were derived from a population-based birth defects registry in Hawaii and comprised all infants and fetuses with anophthalmia and microphthalmia who were delivered during 1986-2001. Anophthalmia and microphthalmia rates per 10,000 births were determined for selected factors, and comparisons were made by calculating the rate ratios and 95% confidence intervals (CIs). RESULTS: Ninety-six cases of anophthalmia and microphthalmia were identified, with a rate of 3.21 per 10,000 live births. The eye defects were isolated in 5 cases (5.2%), and 24 cases (25.0%) had confirmed chromosomal abnormalities. The risk of anophthalmia and microphthalmia varied over time and was significantly higher for live-born infants with low birth weights and gestational ages. The anophthalmia and microphthalmia rates also varied by maternal race/ethnicity, sex, and plurality, although these differences were not statistically significant. CONCLUSIONS: Anophthalmia and microphthalmia frequently occurred with other birth defects, and the rate was consistent with that found in the literature. The risk of defects differed significantly with time period, birth weight, and gestational age. The impact of many factors on anophthalmia and microphthalmia in Hawaii was frequently consistent with that reported elsewhere.

Abnormalities, Multiple↗
PubMed1993

Visual system of a naturally microphthalmic mammal: the blind mole rat, Spalax ehrenbergi.

Retinal projections and visual thalamo-cortical connections were studied in the subterranean mole rat, belonging to the superspecies Spalax ehrenbergi, by anterograde and retrograde tracing techniques. Quantitative image analysis was used to estimate the relative density and distribution of retinal input to different primary visual nuclei. The visual system of Spalax presents a mosaic of both regressive and progressive morphological features. Following intraocular injections of horseradish peroxidase conjugates, the retina was found to project bilaterally to all visual structures described as receiving retinal afferents in non-fossorial rodents. Structures involved in form analysis and visually guided behaviors are reduced in size by more than 90%, receive a sparse retinal innervation, and are cytoarchitecturally poorly differentiated. The dorsal lateral geniculate nucleus, as defined by cyto- and myelo-architecture, cytochrome oxidase, and acetylcholinesterase distribution as well as by afferent and efferent connections, consists of a narrow sheet 3-5 neurons thick, in the dorsal thalamus. Connections with visual cortex are topographically organized but multiple cortical injections result in widespread and overlapping distributions of geniculate neurons, thus indicating that the cortical map of visual space is imprecise. The superficial layers of the superior colliculus are collapsed to a single layer, and the diffuse ipsilateral distribution of retinal afferents also suggests a lack of precise retinotopic relations. In the pretectum, both the olivary pretectal nucleus and the nucleus of the optic tract could be identified as receiving ipsilateral and contralateral retinal projections. The ventral lateral geniculate nucleus is also bilaterally innervated, but distinct subdivisions of this nucleus or the intergeniculate leaflet could not be distinguished. The retina sends a sparse projection to the dorsal and lateral terminal nuclei of the accessory optic system. The medial terminal nucleus is not present. In contrast to the above, structures of the "non-image forming" visual pathway involved in photoperiodic perception are well developed in Spalax. The suprachiasmatic nucleus receives a bilateral projection from the retina and the absolute size, cytoarchitecture, density, and distribution of retinal afferents in Spalax are comparable with those of other rodents. A relatively hypertrophied retinal projection is observed in the bed nucleus of the stria terminalis. Other regions which receive sparse visual input include the lateral and anterior hypothalamic areas, the retrochiasmatic region, the sub-paraventricular zone, the paraventricular hypothalamic nucleus, the anteroventral and anterodorsal nuclei, the lateral habenula, the mediodorsal nucleus, and the basal telencephalon.(ABSTRACT TRUNCATED AT 400 WORDS)

Adaptation, Physiological↗
PubMed1995

Normalization of mineral homeostasis after reversal of osteopetrosis.

Whether a radiographic and histologic cure of osteopetrosis includes normalization of mineral homeostasis remains unknown. Thus, we explored the extent of defective mineral metabolism in the microphthalmic (mi/mi) mouse before and after cure. Under basal conditions mi mutants exhibit normocalcemia, hypophosphatemia, and elevated renal 25-hydroxyvitamin D-1-hydroxylase activity. However, administration of PTHrP (3 micrograms/h x 24 h) further stimulated enzyme activity in mi mutants with active disease, to a level no different than that in treated normals. Serum phosphorus levels also declined in mi/mi mice following PTHrP, suggesting a normal renal response to this hormone. In contrast, failure to suppress enzyme function in mi/mi mice following prolonged calcitriol infusion indicates that the observed enhancement of 1,25-dihydroxyvitamin D production occurred secondary to autonomous parathyroid function and/or nonparathyroid hormone-related stimuli. Although an increased fractional excretion and decreased tubular reabsorption of phosphate were demonstrated in mi/mi mice, serum PTH levels were no different in mi mutants compared with normal littermates. Following skeletal cure, the mi/mi mice surprisingly display normal serum phosphorus levels and renal enzyme activity. Moreover, treatment restored normal responsiveness to calcitriol suppression and maintained normal PTHrP responsiveness of enzyme activity. These data indicate that the cure of osteopetrosis in the mi mutant is universal and includes normalization of serum phosphorus and renal 25-hydroxyvitamin D-1-hydroxylase. Furthermore, these data suggest that phosphate depletion of unknown origin is the likely cause of elevated enzyme activity in this murine osteopetrotic mutant.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed1977

Genetic and experimental studies on three associated mutant genes in the Mexican axolotl: st (for stasis), mi (for microphthalmic) and h (for hand lethal).

Three mutant genes, st, mi, and h, were discovered in an axolotl male received from Mexico City. All three are recessive to their normal alleles, and appear to segregate independently. Larvae homozygous for st (for stasis) suffer blockage of the circulation at hatching or shortly after, and the majority soon die; any surviving live only a few weeks at most. The mi/mi (microphthalmic) can be identified at the feeding stage. None survives more than a few days. The h/h (hand lethals) live until the digits have appeared on the forelimb. They may then be recognized by the thumb-like orientation of digit 1. Transplants from st/st embryos into normal produce normal structures which persist indefinitely. Those from mi/mi and h/h donors do not survive. The structures (forelimb, gills) derived from h/h donors grow for a relatively long time, and their final death and degeneration result in defects leading to death of most of the recipients. Parabiosis is of no benefit to st/st or h/h mutants and leads to the death of the normal twin; mi/mi mutants undergo a gradual absorption by the normal twin.

Ambystoma↗
PubMed1982

Site of gene action of the white allele (Miwh) of the microphthalmia locus: a dermal-epidermal recombination study.

The white allele Miwh of the microphthalmia locus, when homozygous, causes a complete absence of neural crest-derived melanocytes in skin and internal organs. The site(s) of gene action of Miwh on melanoblast differentiation were examined by making dermal-epidermal recombinant grafts with skin from 13-14-day embryos of the following genotypes: normal (+/+), heterozygous white (Miwh/+), homozygous white (Miwh/Miwh), and dominant spotting (W/W). Based on results from these grafts, the following conclusions were reached: Miwh/Miwh epidermis is as effective as W/W epidermis in supporting the differentiation of +/+ follicular melanocytes. Miwh/Miwh dermis is completely permissive to in situ differentiation of +/+ follicular melanocytes. Thirteen-fourteen-day embryonic Miwh/Miwh skin, both epidermis and dermis, alters of blocks the differentiation of +/+ melanoblasts into dermal melanocytes. By 13 days of development, melanoblasts from both Miwh/+ and Miwh/Miwh skin, even when presented with a permissive W/W environment, are irreversibly redirected into abnormal developmental pathways resulting in either a reduction in follicular pigmentation (Miwh/+) or a complete absence of follicular melanocytes (Miwh/Miwh).

Alleles↗
PubMed1983

Effects of microphthalmic white (Miwh) on the number and function of cutaneous melanocytes.

Microphthalmic white (Miwh), when heterozygous, causes dilution of black fur to a uniform gray color. Miwh/+ also reduces the coloration of ear and tail skin. The present study, a quantitative assessment of the effects of Miwh/+ on cutaneous melanocytes, demonstrates that the primary effect of Miwh/+ on cutaneous pigmentation is to reduce the number of epidermal melanocytes. There is also indirect evidence that Miwh/+ reduces the rate of melanosome production within follicular melanocytes. These actions of Miwh/+ cause both lightened coloration of ear and tail skin and the deposition of fewer numbers of smaller melanosomes within the hair.

Animals↗
PubMed1981

Prenatal development of the microphthalmic eye in the golden hamster.

Prenatal development of the eye in a microphthalmic hamster strain ("anophthalmic white") is compared with established normal developmental periods. The mutant eye primordium is first distinguished at an average of ten gestational days (Period 6) by an incompletely invaginated optic cup, uniformly pseudostratified outer neuroepithelial layer and widely separated margins of the optic fissure. The outer layer of the mutant cup subsequently becomes abnormally thickened, especially posteriorly and midventrally, and, except in a few eyes with localized imperfect fusion, the optic fissure is unfused at twelve days (Period 9), by which time fusion is normally complete. At 13 to 15 days (Period 10-11) the fissure is unfused or irregularly fused in regions of variable location and extent. The occurrence of fissure fusion with concomitant loss of continuity between inner and outer epithelial layers is generally restricted to expanded anterior regions in 14-16 day (Periods 11-12) eyes. The presence of presumptive neural retina in the outer layer of the cup characterizes the mutant eye; and to varying degrees, in day 13-16 eyes, the presumptive neural retina (1) provides persistent continuity between the two cup layers, (2) forms both fused and unfused margins of the optic fissure, and (3) extends into an outer position of the optic cup. As early as 13 days (Period 10), nerve fibers are present in the outer layer of the cup, and by the last prenatal and first postnatal days (Period 12), ectopic nerve fiber bundles are widely distributed.

Animals↗
PubMed1981

Morphogenesis of the hereditary microphthalmia in a new strain of rat.

Morphogenesis of the eye was studied in a new strain of microphthalmic rat. Abnormalities were noted immediately after the formation of the optic cup. The inner layer in the central part of the optic cup was relatively thick and contained many mitotic figures, whereas that of the marginal part was thin and contained only a few. The transitional point in the inner layer between the central and the marginal parts was well marked. This is evidently due to the extreme growth inhibition of the inner layer at the marginal part. At the early developmental stage, an area of the inner layer corresponding to the transitional point protruded toward the lens because the central part of the inner layer continued to differentiate. The differentiation and the protrusion of the inner layer proceeded variably at the later stages depending on the degree of the growth inhibition. The eyes were classified into three groups: Group A-the retina was recognized as a cyst consisting of the pigment layer and the pigment-layerlike structure which originated from the inner layer; group B-the neural retina and its layered structure were inverted; group C-abnormalities, such as the destruction of the lens, were observed. Although previous authors who studied eye mutants suggested the vascular abnormality as the primary cause of the production of abnormal eyes, we feel that this is not the case in our animals.

Animals↗
PubMed2026

Genomic Profiling of Anophthalmia/Microphthalmia-Associated CNVs Reveals Complex Genotype-Phenotype Correlations and Incomplete Penetrance.

BACKGROUND: Anophthalmia/microphthalmia (A/M) is a severe congenital ocular malformation characterized by the complete absence or small size of the eye bulb. Interpreting copy number variations (CNVs) in A/M is challenged by variable genotype-phenotype correlations and reduced penetrance. This study investigated the genetic etiology of A/M-associated CNVs. METHODS: Genomic profiling was performed on four unrelated families presenting with ocular anomalies or harboring A/M-susceptible CNVs. Variants were evaluated by integrating American College of Medical Genetics and Genomics (ACMG) guidelines with clinical phenotypes and familial segregation. RESULTS: An inherited 8.13 Mb deletion (8p23.3p23.1) in Patient 1 was excluded due to genotype-phenotype mismatch. Patients 2 and 3 harbored de novo pathogenic deletions involving OTX2 (14q22.3) and SOX2 (3q26.33), causing typical A/M. Case 4 revealed a 14q22.2q23.1 deletion encompassing OTX2 in a fetus and mother without ocular anomalies, consistent with the incomplete penetrance of OTX2-related microphthalmia. Thus, CNV-induced haploinsufficiency causes A/M with high phenotypic variability. CONCLUSION: Accurate CNV interpretation requires robust genotype-phenotype correlation and careful assessment of incomplete penetrance to prevent diagnostic pitfalls and improve genetic counseling.

Female↗
PubMed1982

Chondro-osseous changes in Cerebro-Oculo-Facial-Skeletal (COFS) syndrome.

Radiological and pathological findings were described in three cases of COFS syndrome. Early diagnosis of this syndrome is possible by the recognition radiologically of the characteristic proximal displacement of second metatarsals and pathologically by the extensive cell necrosis in the iliac crest biopsy. Pathological findings, including the presence of nuclear bodies in chondrocytes and amianthoid fibres surrounding necrotic cartilage cells, are compatible with a primary degenerative/deformative disorder. The aetiology of this syndrome is unknown.

Abnormalities, Multiple↗