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Results for “Phenotypic variability”

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PubMed1982

[Immunological classification of acute lymphoblastic leukemias (ALL) in childhood. Origin and clinical significance of phenotypic variability].

Leucemic cells in 54 children with ALL have been typed immunologically by conventional antisera, monoclonal antibodies and receptor tests as c-ALL (62.5%), T-ALL/NHL (18.5%), B-ALL (1.9%) and AUL (16.6%), respectively. The different subtypes showed a noteworthy heterogeneity in receptor patterns which may reflect an arrest in discrete differentiation stages within the maturation pathway of a lymphoid cell population. The characteristic set of clinical symptoms of T-cell neoplasias could once again be confirmed. Of interest is a clear trend for a less favourable outcome in AUL as compared to c-ALL and in NHL versus ALL as a whole, whereas no difference could be found between T-ALL and non T-ALL during therapy. Immunological typing of ALL is of clinical importance as entities with different biological behaviour and, correspondingly, different therapeutical requirements can be distinguished.

Adolescent↗

PubMed1992

[Structure of phenotypic variability in readiness potential in 6-7 year-old children].

This report is a part of a larger project, the major purpose of which is a longitudinal study of developmental changes in genetic control of variation in Bereitshaft potentials (BP). 15 pairs of MZ and 15 pairs of DZ twins aged 6-7 years participated in the BP study. 2 second epochs of EEC time-locked to the movement were digitized off-line at 500 Hz (DAS-16G "Metrabyte"), for 1500 msec, prior to and 5000 msec after movement. A complex BP waveform with the positive components was discovered in young children. We fitted four basic models to the twin data for each of the BP in F3, F4, C3, C4. Since the models (VA, EW) in F3, F4, C3 and (EB, EW) in C4 fit very well and cannot be improved markedly by adding the most important alternative parameters, we conclude that variation of BP of F3, F4, C3 is best explained by a very simple genetic model, and variation of BP of C4 is best explained by a simple environmental model.

Child↗

PubMed1996

Phenotypic variability in male patients carrying the mutant ornithine transcarbamylase (OTC) allele, Arg40His, ranging from a child with an unfavourable prognosis to an asymptomatic older adult.

In five different Japanese families, we identified six male hemizygotes (aged 6, 9, 15, 17, 56, and 65 years) and a putative candidate (aged 48 years), carrying a mutant allele of the ornithine transcarbamylase (OTC) gene, a G to A substitution at nucleotide 119 in exon 2 generating histidine in place of arginine. OTC activity in the necropsied liver tissue was reduced to approximately 12% of the control and that of COS 1 cells transfected with Arg40His OTC cDNA was 10.2 +/- 1.8% of the control transfected with wild type OTC cDNA. Clinical features ranged from death during a hyperammonaemic attack (a 9 year old) to a 65 year old asymptomatic man. We consider that the amount of protein ingested by these subjects may be one predisposing factor leading to the manifestation of this disease.

Adolescent↗

PubMed1998

[Glutaric aciduria type 1: phenotypic variability. Report of 6 patients].

We report six patients with glutaric aciduria type 1 in four families. The patients had marked clinical variability, even within families. Three of the patients studied were normal until the onset of neurologic abnormalities, that presented as an encephalitis-like illness in the first year of age. One patient had an early and important developmental delay, but never suffered an encephalopathic crisis. Two patients have intellectual preservation; one of them has a mild tremor and choreoathetosis since the first year of age, and the other had only two afebrile seizures in infancy and no other neurologic signs. Three patients are severely handicapped, with a severe dystonic-dyskinetic disorder and unable to even sit. All the six patients have macrocephaly and in all the computed tomography showed enlarged CSF spaces and sulcal separation over the frontal and temporal lobes. Urine organic acids study of all patients showed large quantities of glutaric acid.

Adult↗

PubMed2004

Phenotypic variability of non-syndromic hearing loss in patients heterozygous for both c.35delG of GJB2 and the 342-kb deletion involving GJB6.

Mutations in GJB2, encoding the gap junction protein connexin 26, are the most common cause of inherited non-syndromic hearing loss (NSHL), with a broad spectrum of mutations leading to recessive as well as dominant forms. It has been shown that patients who are compound heterozygous for a 342-kb deletion (Delta(GJB6-D13S1830)) involving a large portion of the 5'-part of GJB6, encoding connexin 30, and a GJB2 mutation develop NSHL due to a trait with a digenic pattern of inheritance. We have used a mutation-specific polymerase chain reaction assay to screen NSHL patients for the presence of Delta(GJB6-D13S1830) and identified two families segregating both c.35delG in GJB2 and Delta(GJB6-D13S1830). Remarkably, the severity of hearing loss due to heterozygosity for c.35delG in GJB2 in conjunction with Delta(GJB6-D13S1830) is considerably different in members of the two families, ranging from congenital deafness in one to moderate/severe hearing loss with congenital onset in the other case.

Adolescent↗

PubMed2000

Pendred syndrome: phenotypic variability in two families carrying the same PDS missense mutation.

Pendred syndrome comprises congenital sensorineural hearing loss, thyroid goiter, and positive perchlorate discharge test. Recently, this autosomal recessive disorder was shown to be caused by mutations in the PDS gene, which encodes an anion transporter called pendrin. Molecular analysis of the PDS gene was performed in two consanguineous large families from Southern Tunisia comprising a total of 23 individuals affected with profound congenital deafness; the same missense mutation, L445W, was identified in all affected individuals. A widened vestibular aqueduct was found in all patients who underwent computed tomography (CT) scan exploration of the inner ear. In contrast, goiter was present in only 11 affected individuals, who interestingly had a normal result of the perchlorate discharge test whenever performed. The present results question the sensitivity of the perchlorate test for the diagnosis of Pendred syndrome and support the use of a molecular analysis of the PDS gene in the assessment of individuals with severe to profound congenital hearing loss associated with inner ear morphological anomaly even in the absence of a thyroid goiter.

Adolescent↗

PubMed1998

Ataxia with isolated vitamin E deficiency: heterogeneity of mutations and phenotypic variability in a large number of families.

Ataxia with vitamin E deficiency (AVED), or familial isolated vitamin E deficiency, is a rare autosomal recessive neurodegenerative disease characterized clinically by symptoms with often striking resemblance to those of Friedreich ataxia. We recently have demonstrated that AVED is caused by mutations in the gene for alpha-tocopherol transfer protein (alpha-TTP). We now have identified a total of 13 mutations in 27 families. Four mutations were found in >=2 independent families: 744delA, which is the major mutation in North Africa, and 513insTT, 486delT, and R134X, in families of European origin. Compilation of the clinical records of 43 patients with documented mutation in the alpha-TTP gene revealed differences from Friedreich ataxia: cardiomyopathy was found in only 19% of cases, whereas head titubation was found in 28% of cases and dystonia in an additional 13%. This study represents the largest group of patients and mutations reported for this often misdiagnosed disease and points to the need for an early differential diagnosis with Friedreich ataxia, in order to initiate therapeutic and prophylactic vitamin E supplementation before irreversible damage develops.

Adolescent↗

PubMed2004

Intrafamilial phenotype variability in patients with Gitelman syndrome having the same mutations in their thiazide-sensitive sodium/chloride cotransporter.

BACKGROUND: Gitelman syndrome (GS) most often results from mutations in the thiazide-sensitive sodium chloride cotransporter (NCC). Although the severity of symptoms may vary in patients who have the same mutations, a markedly different clinical presentation in family members with identical mutations is truly rare. METHODS: Five patients (3 women and 2 men) belonging to 2 unrelated Chinese families were investigated. All had chronic hypokalemia, renal potassium (K+) wasting, metabolic alkalosis, and normal blood pressure. Direct sequencing of both the NCC and CLCNKB genes were performed. RESULTS: The probands in each family were men. They had very severe hypokalemia and were symptomatic with episodes of paralysis. They had normal plasma magnesium concentrations, normal calcium excretion rates, and impaired maximal urine concentrating ability. In contrast, female family members were asymptomatic. They had laboratory findings typical of GS--less severe hypokalemia, hypomagnesemia, hypocalciuria, and intact maximal renal concentrating ability. Nevertheless, all patients had the same novel pair of NCC mutations and no mutations detected in CLCNKB. CONCLUSION: Differences in sex may help explain the different clinical presentations in these 2 Chinese families with novel NCC mutations. Hypomagnesemia and hypocalciuria are not always present in patients with GS.

Adult↗

PubMed2004

Mutations in Gng3lg and AGPAT2 in Berardinelli-Seip congenital lipodystrophy and Brunzell syndrome: phenotype variability suggests important modifier effects.

Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder caused by mutations in AGPAT2 and Gng3lg. We screened for mutations in AGPAT2 and Gng3lg in 26 families with CGL and one family with Brunzell syndrome. We found mutations in either AGPAT2 or Gng3lg in all but four probands, including three novel mutations in AGPAT2, A712T (Lys215X), IVS3-1G-->C, and C636A (Phe189X). In three siblings with Brunzell syndrome, we identified a splice site mutation (IVS4-2A-->G) in AGPAT2, showing that AGPAT2 mutations can also cause Brunzell syndrome. Eighteen CGL patients from 15 families from the same region of northeastern Brazil were homozygous for a frameshift mutation (669insA of AF05149) in Gng3lg. Despite having the same mutation, the subjects had widely divergent clinical manifestations. In our subjects, there did not appear to be any distinguishing clinical characteristics between CGL subjects with AGPAT2 or Gng3lg mutations with the exception of mental retardation in carriers of Gng3lg. In summary, mutations in AGPAT2 and Gng3lg are approximately equally represented in CGL; despite harboring the same Gng3lg mutation, subjects may have widely divergent clinical manifestations, suggesting modifying influences of other genes and/or environment; and Brunzell syndrome may be caused by a mutation in AGPAT2.

1-Acylglycerol-3-Phosphate O-Acyltransferase↗

PubMed1996

Unstable triplet repeat and phenotypic variability of spinocerebellar ataxia type 1.

A Siberian kindred with spinocerebellar ataxia genetically linked to the SCA1 locus on chromosome 6p has been screened for the CAG triplet expansion within the coding region of the SCA1 gene. The kindred includes 1,484 individuals, 225 affected and 656 at risk, making this collection the largest spinocerebellar ataxia type 1 (SCA1) pedigree known. Each of the studied 78 SCA1 patients carried an expanded allele containing a stretch of 39 to 72 uninterrupted CAG repeats. Normal alleles had 25 to 37 trinucleotide repeats. Expanded alleles containing 40 to 55 repeats were found in 26 at-risk relatives. The number of CAG repeats in the mutated allele was inversely correlated with age at disease onset. Cerebellar deficiency was present in each patient and its severity was moderately affected by the number of CAG repeats. In contrast, the associated signs, dysphagia, diffuse skeletal muscle atrophy with fasciculations, and tongue atrophy were absent or mild in patients with low CAG repeat numbers, but severely complicated the course of illness in patients with a larger number of repeat units. One female mutation carrier was asymptomatic at age 66, more than 2 standard deviations beyond the average age of risk, suggesting incomplete penetrance. In 2 symptomatic individuals who had an expanded number of CAG repeats on both chromosomes, age at onset, rate of progression, and clinical manifestation corresponded to the size of the larger allele.

Adolescent↗

PubMed2002

Phenotypic variability among first-degree relatives with carnitine palmitoyltransferase II deficiency.

Carnitine palmitoyltransferase (CPT) II deficiency disorders are clinically very variable. To examine the cause(s) of variable symptoms in first-degree relatives with CPT II deficiency, four sisters with various combinations of mutations and polymorphisms in the CPT2 gene were studied, together with 20 sedentary and 24 trained healthy female subjects. One sister, whose symptoms began at age 7 years, was more severely affected than her older sister, whose symptoms began at age 16 years; both were compound heterozygotes for the common S113L mutation and Q413fs, and for the common CPT2 polymorphisms, V3681 and M647V. A third sister became hypoglycemic with fasting, was heterozygous for the S113L mutation, and homozygous for the polymorphism variants. The fourth sister was asymptomatic, heterozygous for the Q413fs mutation, and homozygous for the normal polymorphisms. Residual CPT II activity in skeletal muscle and cultured skin fibroblasts from the two myopathic sisters, and palmitate oxidation in fibrobasts, were abnormally low; cellular and total body fat oxidation were also diminished. Muscle function and fat oxidation were nomal at rest, but a switch to carbohydrate utilization occurred at lower exercise intensities than in sedentary and trained individuals, respectively. Reliance on carbohydrates during stress and hormonal alterations may explain, in part, the variance in ages of onset and serverity of symptoms in myopathic patients.

Adult↗

PubMed1998

Phenotypic variability in fatal familial insomnia (D178N-129M) genotype.

OBJECTIVE: To report the clinical and pathologic features of patients with the D178N-129M mutation living in Germany. METHODS: Patients with clinically suspected Creutzfeldt-Jakob disease (CJD) were seen in an ongoing, prospective epidemiologic study from June 1993 to August 1997 throughout Germany. Suspect patients were referred to the CJD unit by the participating hospitals or physicians. Patients were seen by a physician, and each patient underwent a detailed neurologic examination. Prion protein gene (PRNP) analysis was performed to distinguish patients with familial forms of CJD. RESULTS: The constellation D178N-129M was identified in eight individuals; in one patient, the diagnosis was made by neuropathologic examination. Four affected men and five women belong to eight unrelated families. A family history of a neurodegenerative disorder was recalled in only five patients. In contrast to the first reported fatal familial insomnia (FFI) patient, none of our patients complained of severe, untreatable insomnia in the early stages. Dysautonomia was observed in varying degrees in most patients. The clinical course of these patients resembled sporadic CJD. In six patients, brain tissue was available for neuropathologic study. In one patient, the neuropathologic examination showed changes that were more reminiscent of forms of sporadic CJD; in the remaining five, the histopathology was typical of FFI. CONCLUSIONS: The clinical presentation in patients with FFI may vary to a great extent. Genotyping of the patients was crucial in providing laboratory confirmation of the diagnosis of FFI, even when there was no family history of a prion disease.

Adult↗

PubMed1988

Bone marrow stromal proteoglycan heterogeneity: phenotypic variability between cell lines and the effects of glucocorticoid.

Hematopoiesis in vivo is dependent upon the interaction of hematopoietic stem cells with a complex microenvironment, of which stromal proteoglycans are an important functional component. Certain bone marrow stromal cell lines provide a microenvironment that supports hematopoiesis in vitro, a function that is dependent upon glucocorticoid supplementation. Proteoglycan synthesis in the hematopoietic-supportive D2XRII, Bl6 and 14F1 bone marrow stromal cell lines was studied by 35S-sulfate precursor labelling and ion-exchange separation, followed by isopyknic CsCl density centrifugation and gel filtration HPLC. The effects of glucocorticoid were also investigated. A similar pattern of proteoglycan heterogeneity was observed in all three cell lines, although there was considerable quantitative variation. All cultures synthesized three species of chondroitin/dermatan sulfate (CS/DS) proteoglycans: DS1, excluded from a Bio-Sil TSK-400 HPLC column, and DS2, eluting at Kd = 0.31, were present mainly in the culture media. The smallest (DS3) eluted at Kd = 0.63 and was present mainly in the cell layers. CS/DS species were the major proteoglycans in all cultures. Hydrocortisone-free cultures also synthesized heparan sulfate (HS) proteoglycans, including a cell-associated form (HS1), partially excluded from the TSK-400 column, and a secretory form (HS2), eluting at Kd = 0.15. D2XRII cells also secreted an apparently-unique, high-density proteoglycan, Kd = 0.65, into the culture medium. Hydrocortisone at 10(-6) M virtually abolished HS proteoglycan synthesis in all three cell lines, and altered the pattern of CS/DS proteoglycans in the culture media, increasing the quantity of DS1 and DS3, and reducing the quantity of DS2.

Animals↗

PubMed2004

Mutation screening of USH3 gene (clarin-1) in Spanish patients with Usher syndrome: low prevalence and phenotypic variability.

Usher syndrome type III is an autosomal recessive disorder clinically characterized by the association of retinitis pigmentosa (RP), variable presence of vestibular dysfunction and progressive hearing loss, being the progression of the hearing impairment the critical parameter classically used to distinguish this form from Usher syndrome type I and Usher syndrome type II. Usher syndrome type III clinical subtype is the rarest form of Usher syndrome in Spain, accounting only for 6% of all Usher syndrome Spanish cases. The gene responsible for Usher syndrome type III is named clarin-1 and it is thought to be involved in hair cell and photoreceptor cell synapses. Here, we report a screening for mutations in clarin-1 gene among our series of Usher syndrome Spanish patients. Clarin-1 has been found to be responsible for the disease in only two families: the first one is a previously reported family homozygous for Y63X mutation and the second one, described here, is homozygous for C40G. This accounts for 1.7% of Usher syndrome Spanish families. It is noticeable that, whereas C40G family is clinically compatible with Usher syndrome type III due to the progression of the hearing loss, Y63X family could be diagnosed as Usher syndrome type I because the hearing impairment is profound and stable. Thus, we consider that the progression of hearing loss is not the definitive key parameter to distinguish Usher syndrome type III from Usher syndrome type I and Usher syndrome type II.

Adolescent↗

PubMed1994

Autosomal dominant congenital cataract. Interocular phenotypic variability.

PURPOSE: While intrafamilial morphologic heterogeneity of autosomal dominant congenital cataracts has been well established, interocular variation in individual patients of described pedigrees is small. The authors describe a seven-generation family with 48 of 138 individuals known to be affected with autosomal dominant congenital cataracts of the pulverulent type. Affected patients exhibit a seemingly random expression of either unilateral or bilateral lens opacities. METHODS: Ophthalmic and medical histories were obtained, complete ophthalmologic examinations were performed, blood samples were drawn, and transformed lymphoblastoid lines were established on 53 patients. Eighty-five members of the family were unable to be examined. RESULTS: Twenty-eight of the 53 individuals examined had congenital cataracts. Of these patients, 19 eyes (8 right eyes and 11 left eyes) were unilateral and 9 were bilateral. The clinically unaffected eye in patients with unilateral cataracts showed no evidence of lenticular opacity under detailed slit-lamp examination. Severity of the cataracts included a subtle unilateral zonular cataract with 20/20 visual acuity, bilateral inner fetal nuclear pulverulent opacities with 20/16 visual acuity in both eyes, and dense unilateral and bilateral nuclear cataracts requiring early surgical removal. Incorporating the historic data on patients who were not examined, we found 48 affected members (28 unilateral, 17 bilateral, 3 obligate carriers who were not examined). CONCLUSIONS: Hereditary cataracts typically are symmetric in affected individuals. The authors describe a large pedigree with the apparently random expression of an autosomal dominant gene as either unilateral or bilateral cataract. To their knowledge, this is the first such family described in the literature. Currently, work is under way to determine if the causative gene is linked to previously defined cataract loci on chromosomes 1, 2, or 16.

Cataract↗

PubMed2005

Phenotypic variability of Pseudomonas aeruginosa in sputa from patients with acute infective exacerbation of cystic fibrosis and its impact on the validity of antimicrobial susceptibility testing.

OBJECTIVES: To investigate the variability in antimicrobial susceptibility of Pseudomonas aeruginosa from sputa of patients with cystic fibrosis, to compare testing individual colonies of the same morphotype either separately or combined and to study the reproducibility of testing antimicrobial susceptibility within and between laboratories. METHODS: One hundred and one sputa were cultured. Four colonies of each P. aeruginosa morphotype were suspended. Susceptibility to 12 agents by disc diffusion was tested individually or by pooling the four suspensions. A sputum sample containing four morphotypes of one genotype of P. aeruginosa was used to study reproducibility. Susceptibility was tested in duplicate by eight biomedical scientists in one laboratory and by routine procedures in seven different laboratories. RESULTS: There was a mean of four morphotypes of P. aeruginosa per sputum and three antibiograms per morphotype. In some cases, all four colonies of a single morphotype had different antibiograms. The susceptibility profiles of single isolates of P. aeruginosa correlated poorly with pooled cultures, with the pooled tests missing resistance. Results from one sample tested in duplicate by eight biomedical scientists in one laboratory and in seven other laboratories did not correlate well. The wide range of zone sizes in disc diffusion tests illustrated the variation in susceptibility of 48 colonies from one sputum sample. CONCLUSIONS: The role of conventional antimicrobial susceptibility testing is questionable once P. aeruginosa chronically infects the cystic fibrosis lung. A range of susceptibility patterns is seen, even within a morphotype. Routine test results are not reproducible and underestimate resistance.

Acute Disease↗

PubMed1994

Phenotypic variability of X-protein expression by mastitis-causing Streptococcus agalactiae of serotype NT/X and opsonic activities of specific antibodies.

This study examined the role of antibodies against the X-protein, a surface-localized antigen frequently associated with streptococci causing mastitis in cattle, in the opsonization and phagocytosis of unencapsulated Streptococcus agalactiae. The analysis of various strains of serotype NT/X by flow cytometry, after labeling with a monoclonal antibody to X-protein, revealed that they consisted of a mixture of unstained and stained bacteria. Cloning of mother strains yielded clones of unstained bacteria but not homogeneous clones of stained bacteria. Analysis by ELISA of an unstained clone (4.1) derived from the reference NT/X strain 24/60 indicated that it expressed low amount of X-protein at its surface, about 25 times less than the stained clone 24/60 5.6. Colloidal gold immunolabeling showed the X-protein at the periphery of bacteria (of clone 5.6 and in lower amount of clone 4.1), at a distance from the cell wall. Bovine antibodies (essentially IgG) to X-protein behaved like the monoclonal antibody in the cytometric assay. They activated the classical pathway of complement as shown by the deposition of C1q and C4 on bacteria. Deposition of C4 also occurred on the low-surface-producing clone 4.1 in the presence of antibodies to X-protein, although less efficiently than on the high-surface-producing clone 5.6. When used alone, antibodies promoted the ingestion of bacteria and heat-inactivated immune serum promoted the chemiluminescence activity and the killing by polymorphonuclear cells. In conclusion, antibodies to X-protein induced the deposition of C3 by the classical pathway and were also able to stimulate opsonophagocytic killing of X-bearing S. agalactiae in the absence of deposited C3.

Animals↗

PubMed1989

Development and phenotypic variability of genetically identical half mouse embryos.

The growth and development of three groups of genetically identical F1 C57BL/6J female x SJL/J male mice were compared to examine whether embryo manipulation affects subsequent postnatal growth and development of mammalian embryos: (1) controls--the natural offspring of timed matings, (2) transferred controls--offspring from 2-cell embryos transferred to recipients 1 day asynchronous, and (3) transferred half embryos--offspring developing from one blastomere from the 2-cell stage transferred to recipients 1 day asynchronous. The recipients were C57BL/6J females. No differences were found in the age at eye opening and vaginal opening. At 5 days after birth the median body weights of the controls were lower than the weights of the transferred groups. This result could be explained by the larger litter size in the control group. The overall variances of the body weights did not differ between the groups. By the second week after birth a marked increase in overall variances of body weights of the transferred groups, compared with the control group, was observed. At 5 days after birth, the median tail lengths did not differ between groups, and overall variances were the same. By the second week, the overall variances of the tail lengths of the transferred groups were significantly greater than that of the control group. Possibly the increased overall variances of the body weight and the tail length of the transferred groups are related to the smaller litter size in these groups which affects competition for food and the ambient temperature in the nest. The overall results suggest newborn mice that have developed from half embryos have compensated for their initial deficiency. The intraclass correlation coefficients for body weight and tail length are approximately the same in all groups. Thus, producing artificial identical twins by embryo bisection may not affect their potential usefulness in the design of experiments.

Animals↗