1/10. OXPHOS and mtDNA alterations in a family with spastic paraparesis.OBJECTIVE: To study muscle biopsies in hereditary spastic paraparesis (HSP). methods: We analyzed oxidative phosphorylation activities and mtDNA in 3 individuals from an HSP family. RESULTS: We found histochemical evidence for mitochondrial proliferation and cytochrome c oxidase negative fibers. Biochemically, there was an important reduction of the activities of complexes I and IV in 3 patients. In addition, multiple mtDNA deletions (ranging 4.0-7.0 kb) were found in 2 cases by PCR but not by Southern blot. CONCLUSION: We suggest the use of a muscle biopsy when examining HSP patients. HSP can represent a disorder of nuclear-mitochondrial intercommunication.- - - - - - - - - - ranking = 1keywords = family (Clic here for more details about this article) |
2/10. A novel frameshift mutation of the mtDNA COIII gene leads to impaired assembly of cytochrome c oxidase in a patient affected by Leigh-like syndrome.We report on a novel frameshift mutation in the mtDNA gene encoding cytochrome c oxidase (COX) subunit III. The proband is an 11-year-old girl with a negative family history and an apparently healthy younger brother. Since 4 years of age, she has developed a progressive spastic paraparesis associated with ophthalmoparesis and moderate mental retardation. The presence of severe lactic acidosis and Leigh-like lesions of putamina prompted us to perform muscle and skin biopsies. In both, a profound, isolated defect of COX was found by histochemical and biochemical assays. sequence analysis of muscle mtDNA resulted in the identification of a virtually homoplasmic frameshift mutation in the COIII gene, due to the insertion of an extra C at nucleotide position 9537 of mtDNA. Although the 9537C(ins) does not impair transcription of COIII, no full-length COX III protein was detected in mtDNA translation assays in vivo. Western blot analysis of two-dimensional blue-native electrophoresis showed a reduction of specific crossreacting material and the accumulation of early-assembly intermediates of COX, whereas the fully assembled complex was absent. One of these intermediates had an electrophoretic mobility different from those seen in controls, suggesting the presence of a qualitative abnormality of COX assembly. Immunostaining with specific antibodies failed to detect the presence of several smaller subunits in the complex lacking COX III, in spite of the demonstration that these subunits were present in the crude mitochondrial fraction of patient's cultured fibroblasts. Taken together, the data indicate a role for COX III in the incorporation and maintenance of smaller COX subunits within the complex.- - - - - - - - - - ranking = 0.2keywords = family (Clic here for more details about this article) |
3/10. 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 = 2.3818544504569keywords = family, family member, member (Clic here for more details about this article) |
4/10. Novel heteroplasmic mtDNA mutation in a family with heterogeneous clinical presentations.The protean manifestations of a novel maternally inherited point mutation of the mitochondrial genome are reported. The proband showed isolated, spastic paraparesis. A brother, who had suffered from a multisystem progressive disorder, ultimately died of cardiomyopathy. Another brother is healthy. The proband's mother showed truncal ataxia, dysarthria, severe hearing loss, mental regression, ptosis, ophthalmoparesis, distal cyclones, and diabetes mellitus. A muscle biopsy performed in the proband failed to show the morphological abnormalities typical of mitochondrial disorders; the activities of respiratory chain complexes were normal. However, complex I and IV activities were low in the muscle homogenate of the affected mother and brother. sequence analysis of mtDNA showed a heteroplasmic mutation of the tRNA(Ile) gene (G4284A). The mutation load was approximately 55%, 80%, and 90% in the muscle mtDNA of the proband, his mother, and his affected brother, respectively. Mutation was undetected in the healthy brother, as well as in 100 control samples. Several cybrid clones containing homoplasmic mutant mtDNA from the proband showed significant reductions of complex IV activity and maximum oxygen consumption rate, compared with homoplasmic wild-type clones derived from the same subject.- - - - - - - - - - ranking = 0.8keywords = family (Clic here for more details about this article) |
5/10. presenilin-1 mutation (E280G), spastic paraparesis, and cranial MRI white-matter abnormalities.The authors report unusual presentations of members of an Irish family with familial AD due to an E280G mutation in exon 8 of presenilin-1. One had spastic paraparesis and white matter abnormalities on cranial MRI. A sibling had an internuclear ophthalmoplegia, spastic-ataxic quadriparesis, and "cotton-wool plaques" with amyloid angiopathy on brain biopsy. Another affected sibling also had MRI white matter abnormalities. The MRI findings may reflect an ischemic leukoencephalopathy due to amyloid angiopathy affecting meningocortical vessels.- - - - - - - - - - ranking = 0.20559559546607keywords = family, member (Clic here for more details about this article) |
6/10. transcranial magnetic stimulation study in hereditary spastic paraparesis.The motor-evoked potentials and the cortical excitability by transcranial magnetic stimulation (TMS) were studied in a family with chromosome 2p linked (due to mutations in spastin) and in a family with chromosome 16q linked (due to mutations in paraplegin) hereditary spastic paraparesis (HSP), in order to evaluate the utility of these techniques in identifying the subgroups of the disease. Central motor conduction time and motor treshold to TMS were abnormal in some members of both families; the intracortical inhibition was reduced only in the affected members of the family with chromosome 2p linked HSP, even though the neurological symptoms were sometimes similar and also when clinical features reflecting cortical dysfunction were absent. The motor cortex is differentially involved in the often clinically indistinguishable forms of HSP, and TMS may help in the differential diagnosis.- - - - - - - - - - ranking = 0.61119119093215keywords = family, member (Clic here for more details about this article) |
7/10. Autosomal dominant childhood onset slowly progressive leukodystrophy--a Japanese family with spastic paraparesis, ataxia, mental deterioration, and skeletal abnormality.Autosomal dominant leukodystrophy is an extremely rare disease. Here we report on a dominantly inherited disease in a Japanese family with slowly progressive clinical course. Their symptoms and signs started in early childhood and very slowly progressed. In most patients spastic gait was the initial symptom. Neurological manifestations were characterized by pyramidal signs, ataxia, and mental deterioration. In addition to these neurological signs, the skeletal anomalies such as scoliosis and congenital hip dislocation were also present. MR images showed no abnormality in the early stage, but T2-weighted images revealed high intensity areas in the cerebral and cerebellar white matter, and the dentate nucleus in the advanced stage. Proton MR spectroscopy showed decrease of N-acetylaspartate/creatine ratio and increase of choline/creatine ratio in the advanced stage. Proton MR spectroscopy revealed normal N-acetylaspartate/creatine ratio and increase of choline/creatine ratio in the early stage. We suggested that these patients had abnormality in the white matter when MRI was still normal. We considered that intracranial demyelination was gradually progressed as the symptoms got aggravated.- - - - - - - - - - ranking = 1keywords = family (Clic here for more details about this article) |
8/10. Clinical signs and symptoms in a large hereditary spastic paraparesis pedigree with a novel spastin mutation.The most common form of autosomal dominant hereditary spastic paraparesis (HSP), SPG4, is caused by mutations in the spastin gene on chromosome 2p. This disease is characterized by intra- and interfamilial phenotypic variation. To determine the predictive values of clinical signs and symptoms in SPG4, we examined 43 members of a large pedigree with autosomal dominant HSP. We then identified the genetic etiology of the disorder in this family, a novel nonsense mutation in exon 1 of spastin, carried by 24 of the examined family members. The best clinical predictors of positive gene status were the presence of hyperreflexia in the lower extremities, >2 beats of ankle clonus, pes cavus, bladder symptoms and increased tone in the legs. The mean age of onset was 32.2 /- 7.4 years, but the age of onset was earlier in children from 10 of 12 child-parent gene-positive pairs, with a mean difference of 10.8 /- 3.3 years. The finding of leg weakness was especially common in older-onset affected family member with leg hyperreflexia. These results suggest that specific clinical signs and symptoms may be of value in differentiating individuals affected with SPG4 from family members with nonspecific neurological findings.- - - - - - - - - - ranking = 0.93778973670921keywords = family, family member, member (Clic here for more details about this article) |
9/10. A novel presenilin 1 mutation (Y154N) in a patient with early onset Alzheimer's disease with spastic paraparesis.Early onset familial Alzheimer's disease with spastic paraparesis (FAD-SP) has been associated with mutations of the presenilin 1 gene (PSEN1). We report a pedigree of FAD-SP due to a novel missense mutation of PSEN1 (Y154N). The symptoms of the proband were characterized by presenile dementia in her 40s, preceded by spastic paraparesis in her 30s, whereas the mother of the proband presented with spastic paraparesis in her 40s, followed by symptoms of dementia in her mid 60s. The mutation was found only in the proband, and not in a normal family member, normal Japanese control subjects, patients with sporadic Alzheimer's disease or patients with familial spastic paraparesis without dementia. Thus, Y154N is a novel PSEN1 mutation responsible for FAD-SP of Japanese origin.- - - - - - - - - - ranking = 0.24406471374771keywords = family, family member, member (Clic here for more details about this article) |
10/10. A novel presenilin-1 mutation (Leu85Pro) in early-onset alzheimer disease with spastic paraparesis.BACKGROUND: Early-onset familial alzheimer disease is caused by mutations in the amyloid precursor protein (APP), presenilin-1 (PSEN1), or presenilin-2 (PSEN2) genes. Phenotypic diversity has been reported to be associated with various mutations in PSEN1. Various mutations of PSEN1 have been reported in cases of early-onset alzheimer disease with spastic paraparesis. OBJECTIVE: To describe a novel mutation in the PSEN1 gene associated with early-onset alzheimer disease with spastic paraparesis. PATIENT AND methods: The patient was a 27-year-old man who developed early-onset dementia with spastic paraparesis. We examined sequences of the PSEN1, PSEN2, and APP genes from the patient and his family. To detect a possible mutation effect on the production of amyloid-beta peptide (Abeta), transfected hek293 cells were examined for Abeta42 and Abeta40 production. RESULTS: We found a novel mutation (Leu85Pro) in PSEN1. This mutation influenced the production of Abeta, resulting in a 2-fold elevation of Abeta42 production and of the Abeta42/40 ratio. CONCLUSION: To our knowledge, this is the first report of very early-onset alzheimer disease with spastic paraparesis and with the visual variant form of the disease, which is associated with visuospatial cognitive disorder. The Leu85Pro mutation in PSEN1 was pathogenic.- - - - - - - - - - ranking = 0.2keywords = family (Clic here for more details about this article) |
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