Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1762617 (weakness)
 37,932 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thirty-four women with first recurrence of breast cancer were randomized into two groups, and received either Diethylstilbestrol (DES) 5 mg orally (PO) t.i.d. alone, or in combination with Chlorambucil (CB) 0.1--0.2 mg/kg/day PO. All patients randomized were greater than 5 years postmenopausal at the time of the study and had no prior chemical or hormonal therapy. Estrogen receptors were not available. There was no significant difference between Groups A and B with respect to frequency of objective response or mean duration of that response, with the values for Group A being 46.2% and 4.8 months, respectively, and for Group B, 46.7% and 4.8 months (P greater than 0.05). The most common toxicities noted for both groups were nausea and vomiting, edema, weakness, and thrombophlebitis. The risk of major toxicity necessitating withdrawal from the study was greater in Group B due to the added danger of thrombocytopenia/pancytopenia. The addition of CB to DES does not appear to offer any significant advantage over DES alone in women with first recurrence of breast cancer.
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PMID:Comparison of DES vs DES + chlorambucil in women with first recurrence of breast cancer. 48 Sep 49

Up to 40 percent of postmenopausal women have symptoms of atrophic vaginitis. Because the condition is attributable to estrogen deficiency, it may occur in premenopausal women who take antiestrogenic medications or who have medical or surgical conditions that result in decreased levels of estrogen. The thinned endometrium and increased vaginal pH level induced by estrogen deficiency predispose the vagina and urinary tract to infection and mechanical weakness. The earliest symptoms are decreased vaginal lubrication, followed by other vaginal and urinary symptoms that may be exacerbated by superimposed infection. Once other causes of symptoms have been eliminated, treatment usually depends on estrogen replacement. Estrogen replacement therapy may be provided systemically or locally, but the dosage and delivery method must be individualized. Vaginal moisturizers and lubricants, and participation in coitus may also be beneficial in the treatment of women with atrophic vaginitis.
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PMID:Diagnosis and treatment of atrophic vaginitis. 1083 58

Desmin ( DES) mutations have been recognized as a cause of desmin-related myopathy (OMIM 601419), or desminopathy, a disease characterized by progressive limb muscle weakness and accumulation of desmin-reactive granular aggregates in the myofibers. We have studied three families with skeletal or cardioskeletal myopathy caused by small in-frame deletions in the desmin gene. The newly identified in-frame deletions E359_S361del and N366del alter the heptad periodicity within a critical 2B coiled-coil segment. Structural analysis reveals that the E359_S361 deletion introduces a second stutter immediately downstream of the naturally occurring stutter, thus doubling the extent of the local coiled-coil unwinding. The N366del mutation converts the wild-type stutter into a different type of discontinuity, a stammer. A stammer, as opposed to a stutter, is expected to cause an extra overwinding of the coiled-coil. These mutations alter the coiled-coil geometry in specific ways leading to fatal damage to desmin filament assembly. Expression studies in two cell lines confirm the inability of desmin molecules with this changed architecture to polymerize into a functional filamentous network. This study provides insights into molecular pathogenetic mechanisms of desmin mutation-associated skeletal and cardioskeletal myopathy.
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PMID:Small deletions disturb desmin architecture leading to breakdown of muscle cells and development of skeletal or cardioskeletal myopathy. 1464 96

In 1965, an adult-onset, autosomal dominant disorder with a peculiar scapuloperoneal distribution of weakness and atrophy was described in a large, multi-generation kindred and named 'scapuloperoneal syndrome type Kaeser' (OMIM #181400). By genetic analysis of the original kindred, we discovered a heterozygous missense mutation of the desmin gene (R350P) cosegregating with the disorder. Moreover, we detected DES R350P in four unrelated German families allowing for genotype-phenotype correlations in a total of 15 patients carrying the same mutation. Large clinical variability was recognized, even within the same family, ranging from scapuloperoneal (n = 2, 12%), limb girdle (n = 10, 60%) and distal phenotypes (n = 3, 18%) with variable cardiac (n = 7, 41%) or respiratory involvement (n = 7, 41%). Facial weakness, dysphagia and gynaecomastia were frequent additional symptoms. Overall and within each family, affected men seemingly bear a higher risk of sudden, cardiac death as compared to affected women. Moreover, histological and immunohistochemical examination of muscle biopsy specimens revealed a wide spectrum of findings ranging from near normal or unspecific pathology to typical, myofibrillar changes with accumulation of desmin. This study reveals that the clinical and pathological variability generally observed in desminopathies may not be attributed to the nature of the DES mutation alone, but may be influenced by additional genetic and epigenetic factors such as gender. In addition, mutations of the desmin gene should be considered early in the diagnostic work-up of any adult-onset, dominant myopathy, even if specific myofibrillar pathology is absent.
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PMID:Scapuloperoneal syndrome type Kaeser and a wide phenotypic spectrum of adult-onset, dominant myopathies are associated with the desmin mutation R350P. 1747 Apr 97

Regardless of their origin, neuroactive steroids are capable of modifying neural activities by modulating different types of membrane receptors. Neurosteroids are synthesized de novo in neurones and glia. Steroidogenic enzymes are found in the central nervous system. Classical steroid receptors are localized in the cytoplasm, they exert regulatory actions on the genome, and their activation causes medium- and long-term effects. Non-classical receptors are located within the membrane and act as mediators of short-term effects. Other important players are co-repressors and co-activators that can interfere with or enhance the activity of steroid receptors. Beyond their function in stress, corticosteroids play a very important role in fear, anxiety, and memory functions. Patients with Cushing's syndrome frequently develop mood disorder, reversible brain atrophy with transient memory loss, rarely delirium or psychosis. Well-known peripheral symptom is steroidal myopathy. In patients with Addison's disease the main signs are weakness of muscles, lack of energy, decreased mental functions and reduced quality of life. Estrogen and progesterone have their own respective hormone receptors, whereas allopregnanolone acts via the GABA receptors. These hormones have significant role in the development of brain, the architecture of neural circuits and dendrites, density of axonal connections, and the number of neurons. They influence maturation, neuroprotection, seizures, cognitive functions, mood, anxiety, pain, and restitution of peripheral nerves. Androgens also affect cognitive functions, pain, anxiety, mood, and additionally aggression.
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PMID:[Neurological and psychiatric aspects of some endocrine diseases. The role of neurosteroids and neuroactive steroids]. 1792 Nov 20

Desminopathy is one of the most common intermediate filament human disorders associated with mutations in closely interacting proteins, desmin and alphaB-crystallin. The inheritance pattern in familial desminopathy is characterized as autosomal dominant or autosomal recessive, but many cases have no family history. At least some and likely most sporadic desminopathy cases are associated with de novo DES mutations. The age of disease onset and rate of progression may vary depending on the type of inheritance and location of the causative mutation. Typically, the illness presents with lower and later upper limb muscle weakness slowly spreading to involve truncal, neck-flexor, facial and bulbar muscles. Skeletal myopathy is often combined with cardiomyopathy manifested by conduction blocks, arrhythmias and chronic heart failure resulting in premature sudden death. Respiratory muscle weakness is a major complication in some patients. Sections of the affected skeletal and cardiac muscles show abnormal fibre areas containing chimeric aggregates consisting of desmin and other cytoskeletal proteins. Various DES gene mutations: point mutations, an insertion, small in-frame deletions and a larger exon-skipping deletion, have been identified in desminopathy patients. The majority of these mutations are located in conserved alpha-helical segments, but additional mutations have recently been identified in the tail domain. Filament and network assembly studies indicate that most but not all disease-causing mutations make desmin assembly-incompetent and able to disrupt a pre-existing filamentous network in dominant-negative fashion. AlphaB-crystallin serves as a chaperone for desmin preventing its aggregation under various forms of stress; mutant CRYAB causes cardiac and skeletal myopathies identical to those resulting from DES mutations.
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PMID:Intermediate filament diseases: desminopathy. 1918 Oct 99

Myofibrillar myopathy (MFM) encompasses a genetically and clinically heterogeneous group of inherited or sporadic skeletal muscle disorders characterized pathologically by the presence of myofibrillar dissolution associated with accumulation of myofibrillar degradation products and ectopic expression of multiple proteins especially Z-disk related proteins. Patients with MFM initially present with muscle weakness and commonly developed cardiomypathy in the advanced stage. To date, mutations of genes encoding Z-disk proteins or proteins maintaining myofibrillar integrity including ZASP, MYOT, DES, FLNC and CRYAB underlie MFM. The authors herein report a 29-year-old Thai woman with a clinical diagnosis of autosomal dominant limb-girdle muscular dystrophy (LGMD1) who has one affected grandmother. The patient was subsequently found to have MFM based on her myopathological findings. Analyses of all MFM-genes known to date revealed no mutations. The current case emphasizes the importance of muscle biopsy in LGMD1 patients and a wide range of phenotypic variations among patients with MFM. The causative genes underlying the majority of MFM remain uncovered. Close monitoring of the cardiac function is crucial to prevent mortality among these patients.
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PMID:Myofibrillar myopathy with limb-girdle phenotype in a Thai patient. 1925 8

Desminopathy is a genetically heterogeneous disorder with autosomal dominant pattern of inheritance in most affected families; the age of disease onset is on average 30 years. We studied a patient with a history of recurrent episodes of syncope from infancy who later developed second-degree AV block and restrictive cardiomyopathy; she subsequently suffered several episodes of ventricular tachyarrhythmia requiring implantation of bicameral defibrillator. Neurological examination revealed rapidly progressive bilateral facial weakness, winging of the scapulae, symmetric weakness and atrophy of the trunk muscles, shoulder girdle and distal muscles of both upper and lower extremities. Muscle biopsy demonstrated signs of myofibrillar myopathy with prominent subsarcolemmal desmin-reactive aggregates. Molecular analysis identified a homozygous deletion in DES resulting in a predicted in-frame obliteration of seven amino acids (p.R173_E179del) in the 1B domain of desmin. We describe the youngest known desminopathy patient with severe cardiomyopathy and aggressive course leading to the devastation of cardiac, skeletal and smooth musculature at an early age.
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PMID:Severe infantile-onset cardiomyopathy associated with a homozygous deletion in desmin. 1943 60

Autosomal dominant Emery-Dreifuss muscular dystrophy is caused by mutations in LMNA gene encoding lamins A and C. The disease is characterized by early onset joint contractures during childhood associated with humero-peroneal muscular wasting and weakness, and by the development of a cardiac disease in adulthood. Important intra-familial variability characterized by a wide range of age at onset of myopathic symptoms (AOMS) has been recurrently reported, suggesting the contribution of a modifier gene. Our objective was to identify a modifier locus of AOMS in relation with the LMNA mutation. To map the modifier locus, we genotyped 291 microsatellite markers in 59 individuals of a large French family, where 19 patients carrying the same LMNA mutation, exhibited wide range of AOMS. We performed Bayesian Markov Chain Monte Carlo-based joint segregation and linkage methods implemented in the Loki software, and detected a strong linkage signal on chromosome 2 between markers D2S143 and D2S2244 (211 cM) with a Bayes factor of 28.7 (empirical p value = 0.0032). The linked region harbours two main candidate genes, DES and MYL1 encoding desmin and light chain of myosin. Importantly, the impact of the genotype on the phenotype for this locus showed an overdominant effect with AOMS 2 years earlier for the homozygotes of the rare allele and 37 years earlier for the heterozygotes than the homozygotes for the common allele. These results provide important highlights for the natural history and for the physiopathology of Emery-Dreifuss muscular dystrophy.
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PMID:Modifier locus of the skeletal muscle involvement in Emery-Dreifuss muscular dystrophy. 2106 30

A 17-year-old female presented with diffuse muscle weakness secondary to severe hypokalemia, metabolic alkalosis, and hypertension. Additional findings included delayed puberty with primary amenorrhea. Laboratory evaluation led to a diagnosis of 17 alpha-hydroxylase/17,20-lyase (P450c17) deficiency, a form of congenital adrenal hyperplasia (CAH). Her symptoms and metabolic derangements improved with glucocorticoid replacement to suppress ACTH production and mineralocorticoid excess, although she continues to require antihypertensive therapy. Estrogen replacement was initiated due to sex hormone insufficiency. This rare disorder should be considered when evaluating patients with pubertal delay and hypertension, particularly if there is associated hypokalemia.
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PMID:Pubertal delay, hypokalemia, and hypertension caused by a rare form of congenital adrenal hyperplasia. 2119 Aug 71


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