Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ten new patients with ataxia telangiectasia-like disorder (ATLD) from three unrelated Saudi Arabian families have been identified aged 5-37 representing the largest cohort of ATLD patients ever identified. They presented with an early-onset, slowly progressive, ataxia plus ocular apraxia phenotype with an absence of tumor development, even in the oldest patient. Extra-neurological features such as telangiectasia, raised alpha-fetoprotein and reduced immunoglobulin levels were absent. No translocations were found in the two investigated patients, and the presence of microcephaly was noted in four out of eight ascertained patients. All patients are homozygous for a novel missense mutation (630G-->C, W210C) of the MRE11 gene. The cellular consequences of this amino acid change, localized in the nuclease domain of the Mre11 protein, have been determined in fibroblast cultures established from two individuals. They showed high constitutive levels of Mre11 and Rad50 proteins compared with cells from normal individuals but a very low level of the Nbs1 protein. After exposure to ionizing radiation, a dose-dependent defect in ataxia telangiectasia mutated (ATM)-serine 1981, p53-serine 15 and Chk2 phosphorylation, and p53 stabilization were noted, together with a failure to form Mre11 foci and enhanced radiation sensitivity. Formation of gammaH2AX foci was similar to that seen in normal fibroblasts under the experimental conditions examined. These results emphasize the importance of functional interactions among the three proteins of the Mre11-Rad50-Nbs1 complex and lend support to a role of this complex as a sensor of DNA double-strand breaks, acting upstream of ATM.
 ...
PMID:Identification and functional consequences of a novel MRE11 mutation affecting 10 Saudi Arabian patients with the ataxia telangiectasia-like disorder. 1557 63

Senataxin recently was identified as the mutated gene in ataxia-oculomotor apraxia 2, which is characterized by ataxia, oculomotor apraxia, and increased alpha-fetoprotein levels. In this study, we evaluated 24 ataxic patients from 10 French-Canadian families. All cases have a homogeneous phenotype consisting of a progressive ataxia appearing between 2 and 20 (mean age, 14.8) years of age with associated dysarthria, saccadic ocular pursuit, distal amyotrophy, sensory and motor neuropathy, and increased alpha-fetoprotein levels but absence of oculomotor apraxia. Linkage disequilibrium was observed with markers in the ataxia-oculomotor apraxia 2 locus on chromosome 9q34. We have identified four mutations in senataxin in the French-Canadian population including two novel missense mutations: the 5927T-->G mutation changes the leucine encoded by codon 1976 to an arginine in the helicase domain (L1976R), and the 193G-->A mutation changes a glutamic acid encoded by codon 65 into a lysine in the N-terminal domain of the protein (E65K). The common L1976R mutation is shared by 17 of 20 (85%) carrier chromosomes. The study of this large French-Canadian cohort better defines the phenotype of this ataxia and presents two novel mutations in senataxin including the more common founder mutation in the French-Canadian population.
 ...
PMID:Mutations in senataxin responsible for Quebec cluster of ataxia with neuropathy. 1573 1

A 23 year-old woman presented with dysarthria, hoarseness, dysphasia, ataxia and dyspnoea. MRI showed a mass of heterogeneous intensity at the dorsal medulla oblongata. Laboratory studies revealed high serum alpha-fetoprotein (AFP) and beta-subunit human chorionic gonadotropin (beta-HCG) levels. No other tumours were found on systemic investigation. An intracranial non-germinomatous germ cell tumour (NGGCT) was strongly suspected. The patient received combination chemotherapy using ifosfamide, cisplatin, and etoposide and local irradiation to a total of 52 Gy. Serum AFP and beta-HCG levels normalized after four cycles of chemotherapy and she became asymptomatic apart from mild postural hypotension. A follow-up MRI showed only a tiny residual lesion in the medulla oblongata, which has been stable for more than three years. Surgical resection should be carefully considered in patients with brainstem tumours with elevation of serum tumour markers as chemo- and radiotherapy may be effective for brainstem NGGCT.
 ...
PMID:A tumor in the medulla oblongata producing beta-HCG and AFP. 1609 52

Mutations in the Senataxin gene (SETX) are associated with autosomal recessive ataxia-ocular apraxia 2 (AOA2) and autosomal dominant juvenile ALS (ALS4). Here, the authors describe novel homozygous missense mutations in SETX, M274I, and R1294C, found in two siblings with ataxia, peripheral neuropathy, and increased serum alpha-fetoprotein level and three other siblings with heterozygous missense mutations who were neurologically asymptomatic. The results demonstrate that the double missense mutations are responsible for AOA2 but not for ALS4.
 ...
PMID:Autosomal recessive ataxia with peripheral neuropathy and elevated AFP: novel mutations in SETX. 1671 25

Ataxia-telangiectasia is a multisystem disorder characterized by progressive neurologic impairment, variable immunodeficiency, impaired organ maturation, x-ray hypersensitivity, oculocutaneous telangiectasia, and a predisposition to malignancy. To evaluate clinical and immunologic features of Iranian patients with ataxia-telangiectasia, the records of 104 patients with ataxia-telangiectasia (54 male, 50 female) with the age range of 1.6-23.5 years were reviewed. The Iranian Primary Immunodeficiency Registry was used as the data source. Progressive ataxia was seen in all the patients. Other symptoms were eye movement disorders (n = 84), slurred speech (n = 70), mental retardation (n = 10), and ocular (n = 87) and cutaneous (n = 73) telangiectasia. Three patients developed leukemia and lymphoma, and 17 patients had family history of malignancy. Positive correlation was seen between clinical immunologic symptoms and immunoglobulin deficiencies (P = 0.004). The predominant infections were sinopulmonary and acute and recurrent infections (78 cases). Infections included pneumonia (56 patients), otitis media (34 patients), and sinusitis (50 patients). Average serum alpha-fetoprotein level was 149 +/- 137 ng/dL. The incidence of ataxia-telangiectasia in Iran is high, possibly due to familial marriages. Treatment should be focused on supportive management to prolong survival.
 ...
PMID:Ataxia-telangiectasia in Iran: clinical and laboratory features of 104 patients. 1762 18

Mutations in senataxin have been described recently in 24 cases of French-Canadian descent with ataxia-oculomotor apraxia 2. This recessive ataxia is associated with an elevation in alpha-fetoprotein as in ataxia-telangiectasia. Because ataxia-telangiectasia cells are highly radiosensitive, we used a colony survival assay to measure the radiosensitivity of lymphoblastoid cell lines derived from five French-Canadian patients with ataxia-oculomotor apraxia 2. Two were homozygous for the common French-Canadian L1976R SETX missense mutation; the three others were compound heterozygotes for the common mutation and three different missense mutations. Overall, lymphoblastoid cell lines derived from these cases did not show significant variation from a normal response to 1 Gray of ionizing radiation but the two patients who were homozygous for the common L1976R mutation fell in the intermediate or non-diagnostic range.
 ...
PMID:Ataxia-oculomotor apraxia 2 patients show no increased sensitivity to ionizing radiation. 1772 Apr 98

Ataxia with ocular apraxia type 2 (AOA2) is an autosomal recessive, early onset ataxia caused by mutations in the senataxin (SETX) gene. Ocular apraxia and increased levels of alpha-fetoprotein are characteristic but not obligate markers of the disease. AOA2 is allelic with ALS4, a motor neuron disorder of early onset and autosomal dominant inheritance. We observed a two generation family with ataxia which started at age 14 and 17 in two sibs and at age 23 in their paternal uncle.Oculomotor disturbances included strabismus, saccadic pursuit and gaze evoked nystagmus. MRI revealed severe cerebellar atrophy. All patients presented pronounced peripheral neuropathy with wasting of hand and leg muscles resembling distal motor neuronopathy. Increased alphafetoprotein levels triggered genetic analyses of SETX. We found the sib pair to be compound heterozygous for a single base deletion c.2835delC, resulting in a frameshift mutation and causing nonsense related mRNA decay, and a base exchange c.6106G > A, resulting in abnormal splicing and skipping of exon 15. The similarly affected uncle was homozygous for the c.6106G > A mutation probably due to distant consanguinity in the paternal branch of the family. Pseudodominant occurrence in two generations has not been described before in AOA2 and led, in this family, to false categorization as dominant ataxia before SETX mutations were detected. Clinically this family presented with a phenotype combining typical features of AOA2 and ALS4; thus extending the phenotypic spectrum of SETX mutations.
 ...
PMID:"Pseudodominant inheritance" of ataxia with ocular apraxia type 2 (AOA2). 1835 Mar 59

Ataxia with oculo-motor apraxia type 2 (AOA2) is a recently described autosomal recessive cerebellar ataxia (ARCA) caused by mutations in the senataxin gene (SETX). We analysed the phenotypic spectrum of 19 AOA2 patients with mutations in SETX, which seems to be the third most frequent form of ARCA in Algeria after Freidreich ataxia and Ataxia with vitamin E deficiency. In AOA2 patients, the mean age at onset for all families was in the second decade. Cerebellar ataxia was progressive, slowly leading to disability which was aggravated by axonal polyneuropathy present in almost all the patients. Mean disease duration until wheelchair was around 20 years. Oculo-motor apraxia (OMA) was present in 32% of the patients while convergent strabismus was present in 37%. Strabismus is therefore also very suggestive of AOA2 when associated with ataxia and polyneuropathy even in the absence of OMA. Cerebellar atrophy was more severe in the eldest patients; however it may also be an early sign since it was present in the youngest and paucisymptomatic patients. The initial sign was gait ataxia in all but two patients who presented with head tremor and writer cramp, respectively. Serum alpha-fetoprotein, which was elevated in all tested patients, was a good marker to suggest molecular studies of the SETX gene.
 ...
PMID:Ataxia with oculomotor apraxia type 2: a clinical and genetic study of 19 patients. 1914 56

Friedreich ataxia is the most frequent recessive cerebral ataxia d should always be researched first. Ataxia with isolated vitamin E deficiency and abetalipoproteinemia have a specific treatment. Associated neurological signs such polyneuroapthy, ophtalmologic or oculomotor signs, pyramidal signs, and cerebellar MRI can lead to the etiological diagnosis. Biological tests should be: vitamin E, cholesterol, alpha-fetoprotein levels, acanthocytes, than phytanic acid, cholestanol, lysosomal enzymes. Numerous autosomal recessive cerebellar ataxia remain without etiology.
 ...
PMID:[Autosomal recessive cerebellar ataxias]. 1944 80

Ataxia with oculomotor apraxia type 2 (AOA2), a neurodegenerative disorder with juvenile to adolescent onset is caused by mutations within the SENATAXIN gene ( SETX). We performed molecular analyses in six patients showing clinically an AOA2 phenotype and moderate to significant elevated serum alpha-fetoprotein levels. Sequencing the 24 coding exons and flanking intronic sequences revealed 11 novel DNA variations, including seven unknown missense mutations, a dinucleotide deletion, a four-nucleotide deletion affecting the 5' splice site of exon 22 and two sequence variations, which are considered to be polymorphisms. By molecular testing the clinical diagnosis has been confirmed in all patients.
 ...
PMID:Ataxia with oculomotor apraxia type 2: novel mutations in six patients with juvenile age of onset and elevated serum alpha-fetoprotein. 1956


<< Previous 1 2 3 4 5 Next >>