1/20. Mother-to-child transmitted WT1 splice-site mutation is responsible for distinct glomerular diseases.Mutations in the Wilms' tumor suppressor gene (WT1) are linked with denys-drash syndrome (DDS), a rare childhood disease characterized by diffuse mesangial sclerosis and renal failure of early onset, XY pseudohermaphroditism, and high risk of Wilms' tumor. KTS (lysine-threonine-serine) splice site mutations in WT1 intron 9 have been described in patients with frasier syndrome, another rare syndrome defined by focal and segmental glomerulosclerosis (FSGS), XY pseudohermaphroditism, and frequent occurrence of gonadoblastoma. Cases of frasier syndrome raise the question whether splice site mutations may also be found in XX females with isolated FSGS. A girl (index case) presented with the nephrotic syndrome at 9 mo of age. The diagnosis of DDS was based on the finding of diffuse mesangial sclerosis in the kidney biopsy and of a XY karyotype. The index case's mother had had proteinuria since she was 6 years of age. A renal biopsy was performed when she was 28 and disclosed FSGS. The same splice site mutation in intron 9 (WT1 1228 5 G-->A) involving one allele was found in the child and in her mother, but not in other members of the kindred (including the parents, the two brothers, and the two sisters of the index case's mother) who were free of renal symptoms. Quantification of WT1 KTS/-KTS isoforms in the index case's father and one index case's maternal uncle showed a normal KTS/-KTS ratio of 1.50. In contrast, the index case and her mother had a low ratio (0.40 and 0.34, respectively), within the range reported in frasier syndrome. In conclusion, this study shows that the KTS splice site mutation is not specific for frasier syndrome, but that it can also be found in DDS and in a normal female (XX) with FSGS, a woman who achieved normal pregnancy. It is suggested that WT1 splice site mutations should be sought in phenotypically normal females who present with FSGS or with related glomerulopathies of early onset.- - - - - - - - - - ranking = 1keywords = sclerosis (Clic here for more details about this article) |
2/20. Numerous conglomerate inclusions in slowly progressive familial amyotrophic lateral sclerosis with posterior column involvement.A 59-year-old woman with slow progression of the loss of motor function and predominant lower motor manifestation during a 14-year period showed familial amyotrophic lateral sclerosis (fALS) with posterior column involvement, neuropathologically. Conglomerate inclusions (CIs) were observed in the remaining neurons in various areas, including the spinal anterior horn, posterior horn, Clark's column, accessory cuneate nucleus, tegmental reticular formation, motor nucleus of the trigeminal nerve, nucleus of the facial nerve, hypoglossal nucleus, medial nucleus of the thalamus, dentate nucleus, and motor cortex (Betz cells). Immunohistochemically, it was newly identified that the CIs showed marked immunoreactions with antibodies to phosphorylated and non-phosphorylated neurofilaments and to 64, 120, and 200 kD neurofilaments. The CIs were partially immunoreactive with the anti-ubiquitin antibody, although they reacted only weakly (or not at all) with anti-Cu/Zn superoxide dismutase (SOD1) antibody. Ultrastructurally, the CIs were comprised of neurofilaments. These data suggest that this case might have been different from an example of fALS with Ile 113 Thr mutation in the SOD1 gene.- - - - - - - - - - ranking = 1.6666666666667keywords = sclerosis (Clic here for more details about this article) |
3/20. Mother with amyotrophic lateral sclerosis and daughter with Creutzfeldt-Jakob disease.OBJECTIVE: To describe a mother who had autopsy-proved amyotrophic lateral sclerosis and her daughter who had clinically diagnosed Creutzfeldt-Jakob disease. DESIGN: case reports with molecular genetic analyses. SETTING: A tertiary care center. patients: The mother had progressive upper and lower motor neuron symptoms and signs starting at the age of 54 years. Electrophysiological testing supported the diagnosis of amyotrophic lateral sclerosis. autopsy results confirmed the diagnosis. Her daughter had received injections of human growth hormone prepared from pooled human pituitary glands as a child. At the age of 31 years, she experienced the onset of gait ataxia and dysarthria. cerebrospinal fluid showed the 14-3-3 protein. Cognitive difficulties ensued. She progressed to a nearly akinetic and mute state. She had overt visible fasciculations and muscle atrophy in the legs. MAIN OUTCOME MEASURES AND RESULTS: Neither patient carried a mutation in the prion protein gene. Both were homozygous for methionine at the polymorphic codon 129. Neither patient carried a deletion of the 5 exons of the superoxide dismutase 1 gene. CONCLUSIONS: It is uncertain whether the 2 cases occurred in the same family by chance or whether the patients shared genetic risk factors for the 2 diseases. The possibility that homozygosity at codon 129 is a risk factor for amyotrophic lateral sclerosis is being tested in a case-control study.- - - - - - - - - - ranking = 2.3333333333333keywords = sclerosis (Clic here for more details about this article) |
4/20. Recurrent leg ulcers and arterial thrombosis in a 33-year-old homozygous variant of antithrombin.We report here a homozygous variant case of antithrombin (AT) associated with arterial thrombosis and recurrent leg ulcers. The deep vein thrombosis was recognized by the venogram of his pelvic veins. His leg ulcers were scattered around his left ankle and accompanied by lipodermatosclerosis, which was evident in venous insufficiency. The propositus had developed cerebral infarction 12 years prior to his leg ulcers. Coagulation study showed low heparin cofactor activity of his AT with a normal level of immunoreactive AT. Nucleotide sequence analysis of the exon 2 of his AT gene showed Arg47-Cys mutation, leading to the lack of affinity of AT for heparin. The propositus is a homozygote for this abnormality.- - - - - - - - - - ranking = 0.33333333333333keywords = sclerosis (Clic here for more details about this article) |
5/20. The coexistence of systemic lupus erythematosus and multiple sclerosis in a mother and daughter.The occurrence of both multiple sclerosis (MS) and systemic lupus erythematosus (SLE) has previously been described in several members within the same family and in twins of successive generations, but the finding of both diseases in one patient is a great rarity. We here report on a rare coexistence of MS and SLE both in mother and daughter. Both patients fulfill the diagnostic criteria of primary-progressive subtype of MS as well as SLE. The finding constitutes supporting evidence of a common genetic background for these two autoimmune disorders.- - - - - - - - - - ranking = 1.6666666666667keywords = sclerosis (Clic here for more details about this article) |
6/20. A novel SOD1 gene mutation in familial ALS with low penetrance in females.We identified a novel missense mutation in the Cu/Zn superoxide dismutase gene in a family with amyotrophic lateral sclerosis (ALS). The mutation was a transition of T to C, resulting in a substitution of leucine 126 to serine in exon 5. The family had very unique clinical features of extremely mild severity only in the legs of two male patients with onset of 42 and 52 years old, and their mothers did not develop any symptom even after reaching the age of 80 and carrying the same mutation. The present study suggests that there are other factors that delay or prevent the disease.- - - - - - - - - - ranking = 0.33333333333333keywords = sclerosis (Clic here for more details about this article) |
7/20. A large family with hereditary spastic paraparesis due to a frame shift mutation of the spastin (SPG4) gene: association with multiple sclerosis in two affected siblings and epilepsy in other affected family members.Hereditary spastic paraparesis (HSP) is a clinically and genetically heterogeneous neurodegenerative disorder characterised by progressive lower limb spasticity and weakness. Some forms have been associated with white matter lesions and complex phenotypes. This study was prompted by the diagnosis of multiple sclerosis (MS) in two sisters from a large pedigree with hereditary spastic paraparesis. Twelve affected members of the extended family were examined (MRI and EEG were carried out and evoked potentials measured in five), and historical information was obtained from six affected deceased persons. The inherited disease phenotype was confirmed as autosomal dominant hereditary spastic paraparesis associated with epilepsy in four affected persons. None of the extended family had evidence of MS. Genetic analysis of the family has shown linkage to chromosome 2p and sequencing of the spastin gene has identified a 1406delT frameshift mutation in exon 10. This kindred demonstrates the clinical heterogeneity of HSP associated with spastin mutations. The possible relevance of the concurrence of HSP and MS in the sib pair is discussed.- - - - - - - - - - ranking = 1.6666666666667keywords = sclerosis (Clic here for more details about this article) |
8/20. The occurrence of various collagen diseases in one family: a sister with ISSc, PBC, APS, and SS and a brother with systemic lupus erythematosus.We encountered siblings who had collagen diseases and related symptoms. Case 1 was a 53-year-old woman who had limited cutaneous systemic sclerosis (ISSc) associated with primary biliary cirrhosis (PBC), antiphospholipid antibody syndrome (APS), and subclinical sjogren's syndrome (SS). Case 2 was a 48-year-old man, her younger brother, with systemic lupus erythematosus (SLE) that developed at 32 years of age. Investigation of their family revealed that their mother had Raynaud's phenomenon, arthritis, and subclinical sjogren's syndrome, and that another younger brother of Cases 1 and 2 had Raynaud's phenomenon and general fatigue. HLA analysis revealed that the sister and brother had some identical hla antigens in common, including A2, A33 (19), B67, B44 (12), Cw7, DR2, DR6, DR52, and DQ1. The sister, brother and their mother had common hla antigens including A2, B67, Cw7, DR2, and DQ1. Although Cases 1 and 2 shared the same HLA system, they presented different phenotypes of collagen disease.- - - - - - - - - - ranking = 0.33333333333333keywords = sclerosis (Clic here for more details about this article) |
9/20. Idiopathic portal hypertension in a systemic sclerosis patient heterozygous for factor v Leiden mutation.Here we present a rare case of systemic sclerosis (SSc) with idiopathic portal hypertension (IPH) having factor v Leiden mutation, a well-known genetic risk factor for various venous thromboses. A 53-year-old SSc patient showing huge esophageal varices and splenomegaly without liver cirrhosis was diagnosed with IPH. As heterozygous Leiden mutation was detected, some coagulation abnormality and resultant formation of microthrombi in the branches of portal vein were suggested as a cause of IPH in this case. This is the first report showing the possible association between Leiden mutation and one of the complications of SSc.- - - - - - - - - - ranking = 1.6666666666667keywords = sclerosis (Clic here for more details about this article) |
10/20. 46,XY phenotypic male with focal segmental glomerulosclerosis caused by the WT1 splice site mutation.OBJECTIVE: frasier syndrome is characterized by progressive glomerulopathy due to nonspecific focal and segmental glomerulosclerosis (FSGS), 46,XY sex reversal and the development of gonadoblastoma from dysgenetic gonads. Donor splice site heterozygous mutations in intron 9 of the Wilms' tumor gene (WT1) cause this disease. We investigated whether WT1 mutations showed clinical heterogeneity. patients AND methods: A 6-year-old phenotypic boy was diagnosed as having FSGS. His karyotype was 46,XY. gonadotropin-releasing hormone and human chorionic gonadotropin stimulation tests revealed normal luteinizing hormone, follicle-stimulating hormone and testosterone responses. The other patient was a 7-year-old 46,XY female with FSGS. Prophylactic gonadectomy was performed and gonadoblastoma was found. By polymerase chain reaction and direct sequencing, WT1 was analyzed in these patients. RESULTS AND CONCLUSION: Both patients had IVS9 5G-->A in intron 9 of the WT1. Our study indicates a normal 46,XY phenotypic male patient with FSGS. The phenotypic variations of the WT1 splice site mutations are further expanded.- - - - - - - - - - ranking = 1.6666666666667keywords = sclerosis (Clic here for more details about this article) |
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