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At least 1,495 records · Page 83Linked to original sources
PubMed2004

Inherited Na transport disorders: the taming of the syndromes.

PURPOSE OF REVIEW: The study of inherited renal sodium (Na) transport disorders has greatly benefited from the use of new molecular biology research tools. This review discusses the recent findings that have expanded our knowledge and may impact clinical decision-making. RECENT FINDINGS: The genetic and molecular biology diagnostic tools have to a large extent validated conclusions drawn from physiologic studies that documented suppressed or enhanced Na transport in specific distal nephron segments in various disorders. However, many surprises were also encountered. In several conditions, no mutation in the Na transporter itself was found despite apparent dysfunction of the transporter. Further search has led to discovery of additional mechanisms. Some involve mutations in other transporters, especially potassium (K) and chloride (Cl) channels, which secondarily affect function of the Na transporter by altering electrochemical gradients across the cell membrane. Examples include certain types of Bartter syndrome. In other patients, search for mechanism has led to discovery of novel physiologic regulatory pathways that, if abnormal, will lead to up- or downregulation of an Na transporter. Examples include some types of Bartter syndrome and Gordon syndrome. Genetic diagnosis has also revealed hitherto unexplained phenotypic heterogeneity between patients carrying the same mutation, implying a contributory role for other factors. SUMMARY: Genetic and molecular diagnosis will have an expanding role in the understanding and management of the Na transport disorders. Predicting prognosis and inheritance pattern, as well as treatment plans will in the future be based on genetic diagnosis.

Biological Transport, Active↗
PubMed1998

Inherited demyelinating neuropathies: from gene to disease.

Hereditary peripheral neuropathies have traditionally been classified by the clinical disease pattern and mode of inheritance. It only recently became possible to provide a more precise subdivision of the diseases by the discovery of distinct genetic defects. Most inherited peripheral neuropathies are caused by distinct mutations in the genes of three well known myelin components, peripheral myelin protein 22, P0 and the gap junction protein connexin 32. The present review addresses the expression and functional roles of these myelin components, as well as the putative pathomechanisms caused by distinct mutations in the corresponding genes. Moreover, the suitability of mutant animals, such as knock-out mice and transgenic rodents, as artificial models for these diseases and their use in the study of possible treatment strategies are discussed.

Animals↗
PubMed2002

Evidence for autosomal recessive inheritance of split hand/split foot malformation: a report of nine cases.

Split hand and foot malformation syndrome (SHFM) is characterized by the absence of the central digital rays, deep median cleft, and syndactyly of the remaining digits. The majority of the familial cases are inherited in an autosomal dominant manner. Here we report on nine cases of SHFM in an inbred kindred. A variable intrafamilial expression of the malformation pattern is apparent. Autosomal recessive inheritance and a two-locus model are discussed.

Adult↗
PubMed2003

Mild facial dysmorphism and quasidominant inheritance in Cenani-Lenz syndrome.

Cenani-Lenz syndrome (CLS; MIM 212780) is a rare autosomal recessive syndactyly/synostosis syndrome. No facial dysmorphism was previously noted. We studied two families; in the first an affected female had a previously affected brother and her father was said to have been similarly affected. Extensive inbreeding in this family suggests quasidominant inheritance. In the second family there was a history of a similarly affected sib who, in addition, had genital anomalies and cleft palate. The parents were first cousins. Both probands had similar mild facial dysmorphism; a high broad, prominent forehead, hypertelorism, a depressed nasal bridge, downslanting palpebral fissures, a short nose, a short prominent philtrum and malar hypoplasia. The present report suggests mild facial dysmorphism and quasidominant inheritance in one family with Cenani-Lenz syndrome.

Adult↗
PubMed2003

An Irish three-generation family of Cornelia de Lange syndrome displaying autosomal dominant inheritance.

The existence of familial de Lange syndrome has been documented in sibs and in parent-child families, but the inheritance pattern continues to be the cause of much debate. We describe a classically affected neonate with de Lange syndrome, an affected mother and probably affected maternal grandmother. These cases show evidence for a dominantly inherited syndrome with a de Lange phenotype.

Adult↗
PubMed1995

Molecular insights into the pathogenesis of inherited renal tubular disorders.

Physiologic and biochemical studies have suggested that the inherited disorders cystinuria, Liddle's syndrome, and perhaps Bartter syndrome all result from defects in renal tubular transport processes. With the recent isolation of several candidate transporter genes, these clinically based hypotheses have begun to be confirmed at a molecular level. In addition, the cloning of the water-channel family of proteins has facilitated the characterization of a second gene defect in congenital nephrogenic diabetes insipidus. This review integrates the pathophysiology of these inherited renal tubular disorders with recent molecular genetic discoveries, and provides a starting point for unraveling their pathogenesis at the molecular level.

Humans↗
PubMed2002

Inherited disorders of the H+-ATPase.

PURPOSE OF REVIEW: The alpha-intercalated cell in the distal nephron shares a number of molecular features with the osteoclast, including site-limited proton pumps that are present at high density. These are multisubunit H -ATPases, which are essential for acid-base homeostasis and for the maintenance of normal bone turnover. In recent years it has become evident that some rare inherited human disorders are due to pump dysfunction in kidney or in bone; these are reviewed here. RECENT FINDINGS: The present review provides an overview of acid secretion in both kidney and bone, and describes the recently identified diseases that are associated with mutations in tissue-specific subunits of these pumps. SUMMARY: Elucidation of the molecular bases of a number of inherited renal acidopathies and bone disorders raises the possibility that additional tissue-specific subunits of these important pumps will be identified, gives hope for a better understanding of normal function at the molecular level, and may have implications for future therapeutic development.

Acidosis, Renal Tubular↗
PubMedDate not supplied

Severe 6-thioguanine-induced marrow aplasia in a child with acute lymphoblastic leukemia and inherited thiopurine methyltransferase deficiency.

6-thioguanine (6TG) is undergoing investigation for use in the maintenance phase of acute lymphoblastic leukemia (ALL). Just as with 6-mercaptopurine (6MP), it is be expected that 6TG would cause pancytopenia in individuals with inherited thiopurine methyltransferase (TPMT) deficiency. We report the first case of severe and prolonged pancytopenia caused by 6-thioguanine in an 8-year-old boy with ALL and inherited TPMT deficiency. Neutropenia lasted 67 days, whereas anemia and thrombocytopenia did not recover for 96 days. To obviate this life-threatening complication, clinicians should consider assaying TPMT activity before initiating therapy with 6MP and, particularly, 6TG in children with ALL.

Antimetabolites, Antineoplastic↗
PubMed2000

Inherited thrombophilia and fetal loss.

Acquired thrombophilia is a well-established cause of pregnancy loss. Increasing numbers of recent observations suggest that inherited thrombophilia is not only associated with gestational thromboembolism but is also a major cause of fetal loss. This review focuses on association of fetal loss with inherited thrombophilias, including dysfibrinogenemia and protein C, protein S, and antithrombin III deficiencies. Activated protein C resistance and factor V Leiden mutation are frequent causes of pregnancy loss. Thrombophilic states such as factor V Leiden and hyperhomocysteinemia may also play a role in other gestational vascular complications, including intrauterine growth restriction, preeclampsia, and placental abruption. Preliminary reports suggest that antithrombotic therapy may be of value in this setting. The potential application of antithrombotic modalities to prevent fetal loss in women with thrombophilia is discussed.

Abortion, Habitual↗
PubMed2001

Diagnosis and incidence of inherited von Willebrand disease.

Von Willebrand disease is the most commonly inherited bleeding disorder, caused by the inheritance of a quantitative or qualitative abnormality of von Willebrand factor. Clinical manifestations of this disorder are diverse, and traditional diagnostic tools vary in sensitivity, specificity, and overall usefulness. However, as more accurate diagnostic testing is developed and implemented, determination of the disease's incidence and prevalence will improve, allowing the identification and treatment of patients who suffer from this disorder.

Female↗
PubMedDate not supplied

Modifier locus for mitochondrial DNA disease: linkage and linkage disequilibrium mapping of a nuclear modifier gene for maternally inherited deafness.

PURPOSE: To examine the role of the nuclear genome in affecting the phenotypic expression of the simplest model of a mitochondrial DNA disease, maternally transmitted deafness. METHODS: Linkage analysis in families with maternally inherited deafness associated with the homoplasmic A1555G mutation. RESULTS: Significant linkage and linkage disequilibrium on chromosome 8 was identified. CONCLUSIONS: This finding represents the first identification of a modifier locus for a human mitochondrial DNA disease and supports the concept of mitochondrial DNA diseases having complex genetic inheritance. The eventual identification of this modifier gene will provide insights into the pathophysiological pathways determining the clinical expression of mitochondrial DNA diseases, an important step toward diagnostic and therapeutic interventions.

Cell Nucleus↗
PubMed2006

Should we screen patients for inherited thrombophilia before starting thalidomide?

The authors present a case of refractory multiple myeloma in an elderly patient with heterozygosity for the G20210A mutation of factor II and for the C677T mutation of methylenetetrahydrofolate reductase. This patient developed acute, multiple cerebral infarctions 5 months into the treatment with thalidomide. The patient improved on oral anticoagulation. The authors presume that thalidomide increased the risk of cerebral infarction in this predisposed patient. The presence of increased risk for thrombosis should alert clinicians to screen patients presenting with systemic thrombosis for inherited thrombophilia. This risk increases with the presence of diseases and therapies that predispose for a hypercoagulable state. They suggest that patients required to be on thalidomide should be screened for inherited thrombophilia and should be considered for prophylactic anticoagulation therapy.

Administration, Oral↗
PubMed2004

Genitourinary complications of inherited epidermolysis bullosa: experience of the national epidermylosis bullosa registry and review of the literature.

PURPOSE: We determined the frequency with which 6 genitourinary tract complications (urethral meatal stenosis, urinary retention, bladder hypertrophy, hydronephrosis secondary to ureteral strictures, pyelonephritis and cystitis) occur in inherited epidermolysis bullosa (EB) in the American EB population. MATERIALS AND METHODS: Up to 16 years of longitudinal followup was done in 3,280 consecutively enrolled patients in the National EB Registry, a National Institutes of Health funded epidemiological study covering the entire continental United States. Data were stratified by major EB type and subtype. Frequencies of occurrence were determined for each of 6 genitourinary tract variables and stratified into 10 mutually exclusive, major EB subtypes. RESULTS: Urinary tract complications occurred in a minority of patients across all major EB subtypes with the highest frequency seen in Herlitz junctional EB (JEB-H). Urethral meatus stenosis was the most common complication, occurring in 11.6% and 8.0% of patients with JEB-H and Hallopeau-Siemens recessive dystrophic EB (RDEB), respectively. Urinary retention, hydronephrosis and bladder hypertrophy occurred in 9.3%, 7.0% and 4.6% of JEB-H cases, respectively. In contrast, pyelonephritis and cystitis were most often seen in the setting of generalized EB simplex (Koebner variant) and inversa RDEB. CONCLUSIONS: The urinary tract may be involved in any subtype of inherited EB, although these complications usually arise in patients with the most severe subtypes of junctional and recessive dystrophic disease. Chronic surveillance for the presence of genitourinary tract disease activity is warranted, especially in patients with JEB and RDEB, given the potential for longterm kidney injury if untreated.

Epidermolysis Bullosa↗
PubMed2005

Fibrinogen heterogeneity: inherited and noninherited.

PURPOSE OF REVIEW: Many noninherited or inherited variations have been described in fibrinogen and they may affect the different functions of fibrinogen. RECENT FINDINGS: A number of the acquired variations in fibrinogen affect the properties of the fibrinogen molecule, such as the conversion rate to fibrin and/or the characteristics of the fibrin clot. Also, genetic polymorphisms are known that can affect the function of the fibrinogen molecule. In addition, some other genetic variants are associated with plasma levels of fibrinogen and with the increase of fibrinogen levels during an acute-phase reaction. SUMMARY: In this review the authors discuss the noninherited and inherited variations of fibrinogen and the clinical implications (e.g. when determining the risk of cardiovascular disease).

Alternative Splicing↗
PubMed2006

Inherited disorders of platelets: an update.

PURPOSE OF REVIEW: To overview inherited syndromes that affect platelets and to discuss current data on the molecular origin and management of these rare diseases. RECENT FINDINGS: An increasing number of genes responsible for inherited thrombocytopenias have been identified and these now extend to glycosylation defects. Although Glanzmann thrombasthenia remains the predominant disorder of platelet function, knowledge is increasing of pathologies concerning primary receptors for adhesion and signalling, the activation and secretory pathways, and even the development of procoagulant activity. SUMMARY: These syndromes affect cell adhesion, cell activation, and cell-to-cell contact interactions fundamental in cell biology. Studies on the pathophysiology of alphaIIbbeta3 in platelets have helped unravel the molecular mechanisms of integrin function, and the information gained has resulted in improved antithrombotic therapy. The establishment of national registries and the use of state-of-the-art genomic and proteomic technologies will accelerate progress and help to define how mutations affecting a much larger range of proteins contribute alone or in combination to defining specific platelet phenotypes.

Animals↗
PubMed2005

Muscle imaging in clinical practice: diagnostic value of muscle magnetic resonance imaging in inherited neuromuscular disorders.

PURPOSE OF REVIEW: This review reports on the use of muscle magnetic resonance imaging as a clinical and research tool in inherited neuromuscular disorders. RECENT FINDINGS: Several papers published during the past few years have reported on the value of muscle magnetic resonance imaging in detecting patterns of muscle involvement in various muscular dystrophies and other inherited myopathies. The patterns of muscle involvement observed on muscle magnetic resonance imaging are often specific for distinct genetic entities. SUMMARY: Our review of the literature suggests that muscle magnetic resonance imaging can provide information that is useful in clinical practice and may be used as an additional tool in a diagnostic flow chart to select appropriate genetic and biochemical investigations.

Diagnosis, Differential↗
PubMed2006

Animal models of inherited neuropathies.

PURPOSE OF REVIEW: Mutations in a number of genes have been associated with inherited neuropathies (Charcot-Marie-Tooth or CMT disease). This review highlights how animal models of demyelinating CMT have improved our understanding of disease mechanisms. Transgenic CMT models also allow therapies to be developed in a preclinical setting. RECENT FINDINGS: Rodent models for the most common subtypes of human CMT disease are now available, and two mouse mutants modeling the rare CMT4B subform have lately extended this repertoire. In a peripheral myelin protein 22 kDa (Pmp22) transgenic rat model of CMT1A, administration of a progesterone receptor antagonist reduced Pmp22 overexpression, axon loss and clinical impairments. Dietary ascorbic acid prevented dysmyelination and premature death in a Pmp22 transgenic mouse line. Neurotrophin-3 promoted small fiber remyelination in CMT1A xenografts and sensory functions in CMT1A patients. Gene expression profiling in rodent models of CMT may identify further therapeutical targets. While original classifications distinguish the demyelinating and axonal forms of CMT, recent findings emphasize that axon loss is a common feature, possibly caused by Schwann cell defects rather than demyelination per se. This supports our model that myelination and long-term axonal support are distinct functions of all myelinating glial cells. SUMMARY: Animal models have opened up new perspectives on the pathomechanisms and possible treatment strategies of inherited neuropathies.

Animals↗
PubMed2004

Territory inheritance in clownfish.

Animal societies composed of breeders and non-breeders present a challenge to evolutionary theory because it is not immediately apparent how natural selection can preserve the genes that underlie non-breeding strategies. The clownfish Amphiprion percula forms groups composed of a breeding pair and 0-4 non-breeders. Non-breeders gain neither present direct, nor present indirect benefits from the association. To determine whether non-breeders obtain future direct benefits, I investigated the pattern of territory inheritance. I show that non-breeders stand to inherit the territory within which they reside. Moreover, they form a perfect queue for breeding positions; a queue from which nobody disperses and within which nobody contests. I suggest that queuing might be favoured by selection because it confers a higher probability of attaining breeding status than either dispersing or contesting. This study illustrates that, within animal societies, individuals may tolerate non-breeding positions solely because of their potential to realize benefits in the future.

Animals↗