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PubMed2001

Spontaneous in vivo reversion of an inherited mutation in the Wiskott-Aldrich syndrome.

The Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency disease, arising from mutations of the WAS-protein (WASP) gene. Previously, we have reported that mononuclear cells from WAS patients showed lack/reduced of the intracellular WASP (WASP(dim)) by flow cytometric analysis, and analysis of WASP by flow cytometry (FCM-WASP) was useful for WAS diagnosis. In this study, we report a WAS patient who showed the unique pattern of FCM-WASP. The patient had the small population of normal expression of WASP (WASP(bright)) mononuclear cells together with the major WASP(dim) population. The WASP(bright) cells were detected in T cells, not in B cells or in monocytes. Surprisingly, the molecular studies of the WASP(bright) cells revealed that the inherited mutation of WASP gene was reversed to normal. His mother was proved as a WAS carrier, and HLA studies and microsatellite polymorphic studies proved that the WASP(bright) cells were derived from the patient himself. Therefore, we concluded that the WASP(bright) cells were resulted from spontaneous in vivo reversion of the inherited mutation. Furthermore, the scanning electron microscopic studies indicated that WASP-positive cells from the patient restored the dense microvillus surface projections that were hardly observed in the WASP(dim) cells. This case might have significant implications regarding the prospects of the future gene therapy for WAS patients.

Adult↗
PubMed2002

Genetic causes of inherited cardiac hypertrophy: Robert L. Frye Lecture.

Cardiac hypertrophy is well recognized as a cardiac manifestation of systemic disorders such as hypertension or intrinsic myocardial disease, but it can also reflect an underlying genetic defect. Molecular studies of inherited forms of cardiac hypertrophy have defined 2 novel pathways that lead to cardiac remodeling in adults, discoveries that increasingly provide insights relevant for both diagnosis and management. This article reviews the genetic studies that led to the current molecular understanding of hypertrophic cardiomyopathy and discusses more recently discovered causes of inherited cardiac hypertrophy.

AMP-Activated Protein Kinases↗
PubMed2006

Regulation, cell differentiation and protein-based inheritance.

Recent research using fungi as models provide new insight into the ability of regulatory networks to generate cellular states that are sufficiently stable to be faithfully transmitted to daughter cells, thereby generating epigenetic inheritance. Such protein-based inheritance is driven by infectious factors endowed with properties usually displayed by prions. We emphasize the contribution of regulatory networks to the emerging properties displayed by cells.

Cell Differentiation↗
PubMed2002

Enzyme replacement therapy for Fabry disease, an inherited nephropathy.

Fabry disease, an X-linked lysosomal storage disease, results from the deficient activity of the enzyme alpha-galactosidase A (alpha-Gal A) and the progressive accumulation of globotriaosylceramide (GL-3) and related glycosphingolipids. In classically affected males with this inherited nephropathy, early and marked GL-3 deposition in the podocytes leads to proteinuria in childhood or adolescence. With increasing age, GL-3 deposition in renal microvascular endothelial cells, and to a lesser extent in interstitial and mesangial cells, leads to renal insufficiency in the third to fifth decades of life. Recently identified "renal variants" who lack the classical disease manifestations of acroparesthesias, angiokeratoma, hypohidrosis, and characteristic corneal/lenticular opacities also develop renal failure. In contrast, "cardiac variants" who also lack the classical phenotype, develop proteinuria in adulthood, but survive a normal lifespan without developing renal failure. Here, we review the renal involvement and pathology in the classical, renal and cardiac variant phenotypes, and present highlights of the preclinical studies and clinical trials that demonstrated the safety and effectiveness of recombinant alpha-Gal A replacement for this inherited nephropathy.

Adult↗
PubMed2004

Outcome of five years of accelerated surveillance in patients at high risk for inherited breast/ovarian cancer: report of a phase II trial.

OBJECTIVE: To assess the outcome of accelerated patient surveillance in patients at high risk for inherited breast or ovarian cancer. METHODS: Using stringent inclusion criteria, 57 high-risk patients (7 positive for BRCA1/2 mutations, 39 mutation negative, and 11 unaffected) were recruited from a genetic testing protocol for inherited breast/ovarian cancer and were followed for 5 years (192.5 total patient years). Patients received twice annual physical examinations, imaging studies, measurement of CA125 and CA15-3, psychometric measurements, and unstructured interviews by a psychologist. RESULTS: When mutation (+) and mutation (-) patients were compared, there were no significant differences in the development of disease metastasis, recurrence, or new cancers. No unaffected patients developed cancer. Management of osteoporosis, sexual function, and psychological distress were major concerns. CONCLUSIONS: Our data suggest that all patients with remarkable family history, regardless of their mutation status, may be at substantially increased risk for disease progression and development of new cancers, which is often not ovarian or recurrent breast cancer. Although prophylactic surgery is important in decreasing cancer recurrence in mutation carriers, increased surveillance with physical examinations and psychological support is also valuable and acceptable to such high-risk patients.

Adult↗
PubMed2001

Maternally inherited diabetes and deafness: a multicenter study.

BACKGROUND: Maternally inherited diabetes and deafness (MIDD), which is seen in 0.5% to 2.8% of patients with type 2 diabetes mellitus, is related to a point mutation at position 3243 of mitochondrial (mt) DNA. Its clinical description is incomplete. OBJECTIVE: To study the clinical presentation and complications of diabetes in patients with MIDD and to identify clinical characteristics that may help select diabetic patients for mtDNA mutation screening. DESIGN: Multicenter prospective descriptive study. SETTING: 16 French departments of internal medicine, diabetes and metabolic diseases, or both. PATIENTS: 54 patients with type 2 diabetes mellitus and the mtDNA 3243 mutation. MEASUREMENTS: Characteristics of diabetes, metabolic control (glycosylated hemoglobin level), complications of diabetes, and involvement of other organs. RESULTS: On average, patients with MIDD were young at diabetes onset and presented with a normal or low body mass index. None were obese. Seventy-three percent of probands had a maternal family history of diabetes. Diabetes was non-insulin-dependent at onset in 87% of patients; however, 46% of patients had non-insulin-dependent disease at onset but progressed to insulin therapy after a mean duration of approximately 10 years. Neurosensory hearing loss was present in almost all patients. Eighty-six percent of patients who received an ophthalmologic examination had macular pattern dystrophy (a specific retinal lesion). Forty-three percent of patients had myopathy, 15% had cardiomyopathy, and 18% (9 of 51) had neuropsychiatric symptoms. Although the prevalence of diabetic retinopathy was 8% among patients who received an ophthalmologic examination, lower than expected after a mean 12-year duration of diabetes, prevalence of kidney disease was 28%. This suggests that a specific renal involvement was the result of mitochondrial disease. CONCLUSIONS: Maternally inherited diabetes and deafness has a specific clinical profile that may help identify diabetic patients for mtDNA testing.

Adolescent↗
PubMed1975

Inherited C2 deficiency and systemic lupus erythematosus: studies on a family.

A patient is described in which an inherited defect in the synthesis of C2 complement component coexisted with the disease systemic lupus erythematosus. The family studies show evidence of the autosomal recessive nature of the inheritance of the C2 synthesis defect. Of particular interest was the finding of a great-aunt who also had homozygous C2 deficiency. This great-aunt suffered from discoid lupus erythematosus as well. The occurrence of various autoantibodies in the serum from the family members, the typing for blood groups, HL-A antigens, and some serum protein markers are reported and discussed. The C2 deficiency may be a critical defect in the host defenses to infection that predisposed to the development of autoimmune disease.

Adolescent↗
PubMed1979

The polyglandular failure syndrome: disease inheritance, HLA type, and immune function.

The occurrence of disease and the inheritance of histocompatibility leukocyte antigens (HLA) were evaluated in 11 patients with the polyglandular failure syndrome and 42 of their relatives. The gene frequency of the HLA-B8 allele (seven of 22) and the HLA-A1, B8 haplotype phenotype frequency (five of 11) were increased in patients with polyglandular failure as compared with a control population. Eleven of 42 relatives had a polyglandular failure illness. Disease prevalence correlated with HLA inheritance in some families, but not all. Patients and diseased relatives had a high incidenceof immunologic dysfunction: autoantibodies, including antinuclear antibodies; elevated serum immunoglobulins (three of 16); abnormal skin tests (four of nine). Polyglandular failure appears to be an HLA-B8-associated syndrome with a high prevalence of disease in relatives. Immunologic dysfunction resulting from a gene(s) on chromosome 6, in linkage dysequilibrium with the HLA-B8 allele, may be a factor in the pathogenesis of polyglandular failure illnesses.

Addison Disease↗
PubMed2002

Prenatal diagnosis of acro-dermatoungual-lacrimal-tooth syndrome, a dominantly inherited ectrodactyly.

As part of an assessment for preeclampsia, a prenatal sonogram performed on a pregnant woman at 33 weeks 4 days' gestation showed ectrodactyly in all 4 fetal extremities. The woman's husband had a history of hand abnormalities but was unaware that his condition was genetic. His examination was notable for ectrodactyly, small, peg-shaped teeth, microretrognathia, nail dysplasia, and a history of lacrimal duct blockage in infancy, consistent with a diagnosis of acro-dermato-ungual-lacrimal-tooth (ADULT) syndrome. Acro-dermato-ungual-lacrimal-tooth syndrome is inherited as an autosomal dominant condition. Many of the inherited ectrodactyly syndromes are now known to be due to mutations in the p63 gene. This case, in which a prenatal sonographic diagnosis of ADULT syndrome was made, illustrates the importance of following up on a history of paternal hand anomalies.

Abnormalities, Multiple↗
PubMed1999

Increased susceptibility to constant light in nr and pcd mice with inherited retinal degenerations.

PURPOSE: To determine whether the degenerating photoreceptors in nervous (nr/nr) and Purkinje cell degeneration (pcd/pcd) mutant mice are more susceptible to the damaging effects of constant light than those in age-matched normal mice. METHODS: Beginning at two ages for each mutant, albino nr/nr and pcd/pcd mice were placed into constant fluorescent light at an illuminance of 115 foot-candles to 130 foot-candles for a period of 1 week. Age-matched (usually littermate) normal (+/-) mice were exposed at the same time. The degree of photoreceptor cell loss was quantified histologically by obtaining a mean outer nuclear layer thickness for each animal. The light-exposed mice were compared with age-matched mutant and normal mice that were maintained in cyclic light. RESULTS: The homozygous mutants at each age showed a significantly greater loss of photoreceptor cells caused by constant light exposure than did the normal +/- mice in the same period of light exposure. The nr/nr and pcd/pcd mutants lost two to three times the number of photoreceptor cells than did the +/- mice during the constant light exposure. CONCLUSIONS: It has long been thought that excessive light may be harmful to patients with inherited or age-related photoreceptor degenerations. The present data add to other experimental evidence suggesting that photoreceptors already undergoing inherited or other forms of degeneration may be particularly susceptible to the damaging effects of excessive light.

Animals↗
PubMed1999

The inheritance of migraine with aura estimated by means of structural equation modelling.

Studies of migraine with aura (MA) have shown familial aggregation of the disorder, which cannot be explained by simple mendelian inheritance. The interest in a genetic basis for the disorder has increased after identification of three genetic loci for familial hemiplegic migraine (FHM), which is a rare subtype of MA with autosomal dominant inheritance. Both genetic and environmental factors seem to be important in the expression of MA. To elucidate the molecular pathogenesis of MA, knowledge of the relative role of genetic and environmental factors is essential. Twin studies are a classic way to analyse this. We applied structural equation modelling on MA with twin data obtained from a population based twin register in order to evaluate the effects of genes and environment. The correlation in liability of MA was 0.68 in monozygotic (MZ) and 0.22 in dizygotic (DZ) twin pairs, indicating a high degree of genetic determination in the total variance of liability. The best fitting model combined additive genetic effects and environmental effects that were not shared by the twins. The estimate of heritability was 0.65 and similar in males and females.

Female↗
PubMed1999

Family aggregation and maternal inheritance of Chinese type 2 diabetes mellitus in Taiwan.

BACKGROUND: Type 2 diabetes mellitus (DM) is a well-known familial disease, although the genetics of this complex condition remains unclear. Recent evidence suggests the significance of maternal inheritance. However, the pattern of family aggregation and the influence of other family relatives on the mode of transmission in Chinese patients with diabetes are lacking. METHODS: We interviewed 449 patients (151 men and 298 women) with type 2 DM who were aged between 35 and 74 years with a mean age of 58 +/- 1 years in a referral hospital in central Taiwan. We recorded a detailed family history of diabetes for each patient. RESULTS: Overall, 60% of diabetic patients had at least one diabetic family member. Among these index patients, 22.5% had a diabetic mother compared with 12.0% who had a diabetic father (p < 0.001). Approximately 29% of diabetic patients had at least one diabetic sister compared with 24% who had at least one diabetic brother (p = 0.13). A total of 27% of diabetic men had a diabetic mother, compared with 20% of diabetic women. Women with diabetes had more diabetic sisters than did diabetic men. In contrast, diabetic men had a significantly increased percentage of diabetic family members on the maternal side or paternal uncles or aunts than did diabetic women. The percentage of diabetic patients who had a diabetic mother decreased as their age increased. The maternal effect disappeared in the diabetic patients who were over 65 years old. Statistical differences between diabetic fathers and mothers were observed when DM was diagnosed in patients under 65 years of age. CONCLUSIONS: We documented the presence of family aggregation and significant maternal inheritance in Chinese patients with type 2 DM in Taiwan. Further prospective study is needed to monitor the offspring of diabetic parents and other relatives in order to clarify the true mode of family aggregation and maternal transmission of type 2 DM.

Adult↗
PubMed1999

Directly inherited partial trisomy of chromosome 6p identified in a father and daughter by chromosome microdissection.

Cytogenetic analysis of a 4 year old girl with developmental delay and dysmorphic features showed extra chromosomal material of unknown origin on 20p (46,XX,add(20)(p13)). Familial chromosome studies showed direct inheritance of add(20)(p13) from the father, who had a similar, albeit milder, phenotype. Fibroblast chromosome studies of the father showed no karyotype mosaicism. The additional material could not be identified on the basis of the G banding pattern owing to its small size and ambiguous banding pattern. Chromosome microdissection of the unknown material was performed, the DNA was amplified and labelled using degenerate oligonucleotide primed polymerase chain reaction (DOP-PCR) and reverse painted to the proband's cells to show the karyotype 46,XX,der(20)t(6;20) (p23;p13), conferring partial trisomy 6p and presumed partial monosomy for 20p. Chromosome microdissection has made possible the first reported case of directly inherited partial trisomy 6p.

Child, Preschool↗
PubMedDate not supplied

The inherited long QT syndrome: from ion channel to bedside.

The inherited long QT syndrome is caused by mutations of at least 5 ion channel genes. Mutations of the cardiac sodium ion channel gene and 3 potassium channel genes have been identified to this time. A genetic locus on chromosome 4 has been identified, but no gene has been discovered as of yet. More than 120 mutations of the genes have been discovered. The majority of cases are inherited by autosomal dominant transmission. Syncope occurs in approximately two-thirds of gene carriers, with sudden death in 10% to 15% of untreated patients. The primary electrophysiologic disturbance is delayed recovery of the action potential, because of diverse physiologic perturbations dependent upon the specific ion channel and mutation. The delayed recovery predisposes individuals to the development of early afterdepolarizations and initiation of torsade de pointes arrhythmias. The torsade produces the syncope and sudden death. Patients with self-terminating torsade have syncope, whereas those whose torsade degenerates to ventricular fibrillation experience sudden death. The torsade maintenance appears to be because of complex reentry or repetitive triggered beats, both of which have been proposed as capable of explaining the unique and characteristic QRS morphology of torsade. It is proposed that the degree of dispersion of recovery at the time of torsade determines whether the torsade degenerates to ventricular fibrillation or self-terminates. The signs of long QT syndrome are prolongation of the QT interval on the electrocardiogram and abnormalities of T wave morphology. QTc values average 0.49 seconds and vary somewhat by genotype. Approximately 12% of long QT gene carriers have a normal QTc, < or =0. 44 seconds. Thus, a normal QTc interval does not exclude long QT syndrome. T wave morphology is relatively characteristic for each genotype. Diagnosis is likely with a QTc > or =0.48 seconds in females and > or =0.47 seconds in males. Values between 0.41 and 0.46 seconds require additional evaluation, as the disorder can neither be excluded nor made with those QTc intervals. Diagnosis is enhanced by identification of T wave abnormalities consistent with long QT syndrome. The principal treatment is beta-blocker therapy. Appropriate dosing, with ascertainment of efficacy and compliance with administration, are the key elements in therapeutic success. Molecular physiology-based strategies are being considered, including the use of sodium channel blockers in LQT3 and potassium administration in LQT1 patients.

Adrenergic beta-Antagonists↗
PubMed1999

Laparoscopic prophylactic oophorectomy in women with inherited risk of ovarian cancer.

The aim of this study was to specify the surgical procedure most adapted for prophylactic laparoscopic oophorectomy in patients with an inherited risk of ovarian cancer. This prospective study was based on a series of 27 patients who underwent prophylactic bilateral laparoscopic oophorectomy between September 1995 and January 1998. Nine patients underwent an oophorectomy (33%) and 18 patients an adnexectomy (67%). The laparoscopic procedure was converted into a laparotomy in one patient in whom an ovarian adenocarcinoma was detected during the surgical procedure. During final histologic examination of the ovaries, 23 patients were found to have benign atypical histologic alterations, one patient had an ovarian adenocarcinoma and only three patients (11%) had normal ovaries. In women with an inherited risk of ovarian cancer, during the laparoscopic procedure for prophylactic oophorectomy, the abdomino-pelvic cavity should be thoroughly explored with peritoneal cytology and systematic peritoneal biopsies. The laparoscopic procedure could be converted into a laparotomy if an ovarian cancer is discovered.

Adult↗
PubMed1999

[Inheritance of quantitative traits in hybrid pedigrees: mixed models].

Mixed models have been extended to make them applicable to description of inheritance of quantitative traits in pedigrees obtained via interbreed or interpopulation hybridization. Additional assumptions specify definite relationships between the parameters that characterize the inheritance of the trait in two parental populations. It is assumed that (1) parental populations differ from each other only in the allelic frequencies in the major gene locus and polygenic loci and (2) the patterns of phenotype formation based on an individual genotype and the transmission of genes to the next generation are the same in both parental populations, as well as in their hybrids. Based on these assumptions, the likelihood function for a hybrid pedigree is derived, and the heterosis effect is formalized. The results of this study offer new possibilities for estimating the contribution of the major gene effect to interpopulation and interbreed differences in the expression of quantitative traits.

Female↗
PubMed1999

Linkage of type II and type III cystinuria to 19q13.1: codominant inheritance of two cystinuric alleles at 19q13.1 produces an extreme stone-forming phenotype.

Cystinuria, a renal tubule disease affecting urinary cystine excretion with or without kidney stone formation, previously was mapped to chromosome region 2p.21. Mutations in the gene SLC3A1 or NBAT, the reported candidate gene for cystinuria at 2p.21, have been demonstrated in individuals with the autosomal recessive Type I cystinuria phenotype. Recently, the Type III cystinuria phenotype was mapped to chromosome region 19q13.1. Here we report a kindred of 39 persons in two families of cystinurics, Types II and III, that support linkage to 19q13.1 and exclude 2p.21. Based on a dominant model of inheritance, two-point analysis of the entire pedigree produced a maximum lod score (Z(max)) of 3.82 at marker D19S425. Multipoint analysis yielded a lod score of 4.96 at this marker, and a resultant lod score of 5.90 using a codominant model of inheritance. Furthermore, a candidate gene interval of 8.9 cM, flanked by markers D19S225 and D19S223, was obtained using multipoint and haplotype analyses. Thus, this kindred demonstrates the linkage of Type II cystinuria to 19q13.1 and confirms the linkage of Type III cystinuria at 19q13.1 while excluding the marker D19S225 that was previously included in the critical interval.

Adolescent↗
PubMed1999

The inheritance of the pigment dispersion syndrome in blacks.

PURPOSE: Evidence has indicated that pigment dispersion syndrome (PDS) is inherited as an autosomal dominant disorder in white patients, often with a high degree of penetrance. Because heredity patterns in blacks are unknown, an investigation was carried out to study inheritance of PDS in this population. METHODS: Six unrelated black adults (5 women, 1 man, age range 43-60 years) with PDS were identified from a primary eye care population at an inner city teaching clinic in Chicago, Illinois. Nineteen first-degree relatives (all siblings or children; age range 18-52 years) of these patients subsequently underwent thorough eye examination to look for signs of PDS. RESULTS: Among the relatives, two (12%) showed evidence of the condition (these two patients belonged to different families): one was a 42-year-old daughter of a 60-year-old proband, and the other was the 49-year-old sister of a 47-year-old proband. Both exhibited definite signs of PDS in one eye only. CONCLUSION: Evidence of expression of PDS among family members of black probands with PDS is provided. Incomplete penetrance of PDS among the black pedigrees may be suggested by these data.

Adolescent↗