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PubMed2001

[Glutaric aciduria type I: diagnosis in adulthood and phenotypic variability].

Glutaric aciduria typo I (GA I) is an uncommon metabolic disease with autosomal recessive inheritance. It usually presents in the first years of life and frequently causes movement disorders. Only a few cases have been diagnosed in adulthood. Two siblings who were diagnosed of GA I after a course of more than 20 years are reported here. The elder brother, after 9 months of normal psychomotor development, suffered from an acute encephalopathy with generalized hypotonia and, later on, dyskinetic movements. Throughout the following years severe generalized dystonia developed. The younger brother presented at 16 months with acute encephalopathy, hypotonia and generalized choreoathetoid movements. Cranial computed tomography showed in both patients an slight enlargement of Silvian cisures and diffuse white matter hypodensities. Magnetic resonance imaging performed in the second case disclosed in addition bilateral hyperintensities in putamen and caudate nucleous. At 29 and 24 years of age, respectively, an increased urinary excretion of glutaric and 3-hydroxiglutaric acids was detected in both patients. Glutaryl-CoA deshidrogenase activity in fibroblasts was absent in both. The patients were treated with carnitine and riboflavine, with no response. The present report shows that diagnosis of GA I should be considered in adults presenting a range of movement disorders from childhood.

Adolescent↗
PubMed2005

Intrafamilial variable phenotypic expression of a CIAS1 mutation: from Muckle-Wells to chronic infantile neurological cutaneous and articular syndrome.

Among hereditary inflammatory disorders, Muckle-Wells syndrome, chronic infantile neurological cutaneous and articular syndrome (CINCA), and familial cold urticaria have recently been shown to be caused by dominantly inherited mutations in the CIAS1 gene. Reports suggest that these 3 diseases result from distinct missense mutations, with very few overlapping symptoms. We describe a French family presenting an intrafamilial overlapping clinical phenotype of CINCA and Muckle-Wells syndrome, caused by a mutation in CIAS1 gene. Clinical and genetic observations suggest that Muckle-Wells syndrome, CINCA, and familial cold urticaria are various phenotypic expressions of the same disease.

Adolescent↗
PubMed1993

Functional analysis of the Arg91Gln substitution in the factor VIII binding domain of von Willebrand factor demonstrates variable phenotypic expression.

An Arg91Gln substitution in the mature von Willebrand factor (vWF) has been associated with defective binding of vWF to factor VIII (FVIII). We studied four families with members initially classified as having type I von Willebrand disease (vWD) who were either homozygous or heterozygous for the Arg91Gln change. The first family was the original case described by Nishino et al. (1) where three members were homozygous for the Gln91 allele. They had a low FVIII coagulant activity:vWF antigen (VIIIC:vWFAg) ratio, from 0.29 to 0.44, and the ability of their plasma vWF to bind FVIII was markedly decreased. All the heterozygous members had normal vWF and FVIII levels but the capacity of their plasma vWF to bind FVIII was reduced and intermediate between the homozygous members and normals. The affected individual from the second family was heterozygous for the Gln91 allele and demonstrated a VIIIC:vWFAg ratio of 0.98. The FVIII binding assay confirmed the heterozygous status indicating that the moderately low levels of vWF were due to reduced expression of both alleles. The propositus from the third family was also heterozygous and had below normal levels of vWF as well as a low VIIIC:vWFAg ratio of 0.34; however, FVIII binding to her plasma vWF was similar to that of the homozygous individuals suggesting that Gln91-vWF was the major circulating form. Her daughter who has type I vWD inherited the allele without the Gln91 mutation indicating that the expression of this allele was indeed impaired. The heterozygous patient in the fourth family had a vWF level of 24 U/dl but an VIIIC:vWFAg ratio greater than 2.(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗
PubMed1993

Evidence that methylation of the FMR-I locus is responsible for variable phenotypic expression of the fragile X syndrome.

DNA at the FMR-1 locus was analyzed by Southern blot using probe StB12.3 in an unusual fragile X family with six brothers, three of whom are affected with fragile X to varying degrees, two of whom are nonpenetrant carriers, and one of whom is unaffected. Fragile X chromosome studies, detailed physical examinations, and psychological testing were completed on all six. Two of the affected brothers and the two nonpenetrant brothers were found to be methylation mosaics. The three affected males spanned the phenotypic and cognitive spectrum of the fragile X syndrome. A correlation was seen between the degree of methylation and the phenotypic expression identified in the three affected males. The two males initially classified as nonpenetrant were found to have mild phenotypic expression which consisted of minor cognitive deficits and a partial physical phenotype. These two, who were negative on fragile X chromosome studies, were found on DNA analysis to have large broad smears, with approximately 97% of the DNA unmethylated. The results described here indicate that some "nonpenetrant" carrier males may have varying amounts of methylation of the FMR-1 region, which can result in mild expression of the fragile X syndrome. The apparently mild phenotypic and cognitive expression of the fragile X syndrome in the two males, initially classified as nonpenetrant, who are mosaic for hypermethylation of an expansion of the CGG repeat in the premutation range, indicates that expression of the syndrome is not confined to males with large, hypermethylated expansions (full mutation) but has instead a gradient effect with a threshold for the full expression of the phenotype.

Adult↗
PubMed1996

Oscillatory insulin secretion: a variable phenotypic marker.

Oscillatory secretion of endocrine hormones is a widely recognized phenomenon. In man, as well as other species (dog, monkey), during the basal state insulin secretion is oscillatory and, on average, regular with a 13-min periodicity. In NIDDM there is a loss of regular oscillatory activity, being shorter in duration and irregular in nature. First-degree relatives of NIDDM subjects with normoglycaemia and obese normal subjects also exhibit this change, reverting to the regular oscillatory characteristic following weight loss in the latter group. The regular insulin secretory oscillations seen in the fasting stage in normal subjects are completely lost by raising the basal glucose concentration only marginally to about 6 mmol l-1. Thus, regular oscillations reflect a 'contented' beta-cell. Also, in states of hyperglycaemia, pulsatile exogenous insulin is more effective than continuous administration. Additional studies indicate that it is the periodicity of the insulin secretory oscillations and the rate of rise of the first phase insulin secretion in response to a glucose challenge which are the main candidates for successful signalling. Irregular oscillations of insulin can be used as an early marker of beta-cell under stress, but not as a fixed phenotypic marker.

Activity Cycles↗
PubMed1998

[Phenotypic variability in gag-myc transgenic mice].

The study of neoplastic growth capacity in gag-myc F3-F4 transgenic mice showed that they retain the capacity to develop hyperplasia and benign and malignant tumors same as F0-F2 transgenic mice do. However, the histological spectrum of tumors was much narrower, chiefly, due to the absence of rare patterns. The tumors in F3-F4 transgenic mice were mainly lymphomas and epithelial tumors of endocrine or exocrine glands. The incorporation of gag-myc in the genome of F3-F4 transgenic mice failed to tell on the variation of such quantitative polygenic characteristics as body mass and growth.

Age Factors↗
PubMed1997

Most germ-line mutations in the nevoid basal cell carcinoma syndrome lead to a premature termination of the PATCHED protein, and no genotype-phenotype correlations are evident.

The human homologue of the Drosophila segment polarity gene patched is implicated in the development of nevoid basal cell carcinoma syndrome (NBCCS) and in the genesis of sporadic basal cell carcinomas. In order to examine the phenotypic variability in NBCCS and to highlight functionally important domains of the PTCH protein, we have now screened 71 unrelated NBCCS individuals for mutations in the PTCH exons. We identified 28 mutations that are distributed throughout the entire gene, and most (86%) cause protein truncation. As part of this analysis, we demonstrate that failure of one NBCCS family to show clear linkage to chromosome 9q22.3-31 is most likely due to germinal mosaicism. We have identified three families bearing identical mutations with variable phenotypes, suggesting phenotypic variability in NBCCS is a complex genetic event. No phenotype genotype correlation between the position of truncation mutations and major clinical features was evident. Two missense mutations have been identified, and their location within transmembrane domains supports the notion that PTCH may have a transport function. The preponderance of truncation mutants in the germ line of NBCCS patients suggests that the developmental defects associated with the disorder are most likely due to haploinsufficiency.

Basal Cell Nevus Syndrome↗
PubMed1988

Trisomy 8 mosaicism syndrome. Two cases demonstrating variability in phenotype.

The paper presents clinical manifestations and results of cytogenetic examination of two patients with trisomy 8 mosaicism syndrome. The findings confirm the extreme phenotype variability of this syndrome. Both the first patient, a mentally retarded child with multiple dysmorphic changes, and the second, a 31-year-old woman with normal IQ and hypogammaglobulinemia as a predominant sign, revealed osteoarticular anomalies. Dermatoglyphic studies in both patients were typical for trisomy 8, and correlated with deep skin furrows. The chromosomal analysis was based on two types of lymphocyte cultures: 3-day and 2-day. A decreased percentage of trisomic cells in 3-day cultures in comparison to 2-day cultures may suggest the influence of environmental factors on spontaneous elimination of trisomic cells in vitro.

Abnormalities, Multiple↗
PubMed2007

RCE1 corneal epithelial cell line: its variability on phenotype expression and differential response to growth factors.

BACKGROUND: By serial transfer of rabbit corneal epithelial cells, the spontaneous RCE1 cell line was previously established. These cells mimic the stage-dependent differentiation of the corresponding cell type. METHODS: RCE1 cells were cultured either on plastic culture dishes or on collagen rafts to compare the epithelial ultrastructure after growth on these substrata. Phenotypic variability was studied after subcloning of cells. The differentiation ability of each subclone was determined by Western blot with antibodies against the differentiation-linked keratin pair K3/K12 and by measuring LDH activity and LDH isozymes in cytosolic extracts. The proliferative response of RCE1 cells to EGF, TGFalpha, amphiregulin, bFGF or IL-6 was determined under serum-free culture conditions. RESULTS: Cells grown on collagen rafts formed 5- to 7-layered epithelia with characteristics closer to those found in normal corneal epithelium than cells cultivated on plastic substrata, which formed 3- to 5-layered epithelia. Subcloning experiments demonstrated that every proliferative cell is able to grow and constitute stratified epithelia expressing K3/K12 keratins. LDH levels in RCE1 epithelia were similar to those of cultured or freshly harvested corneal epithelia; however, they showed a slightly altered LDH isozyme set, with prevalence of LDH-3 isoform. Whereas EGF and TGF-alpha were equipotent, amphiregulin elicited a 4-fold lower proliferative response. Also, bFGF was 10-fold less mitogenic than EGF, and IL-6 had the lowest effect with an ED(50) 20-fold lower than EGF. CONCLUSIONS: The results demonstrate that every RCE1 proliferative cell has the ability to generate epithelial sheets. We conclude that EGF and TGF-alpha are the major effectors of RCE1 cell proliferation.

Animals↗