Disease relevance of Ataxia

• The closest homolog to TEL1 is the human ataxia telangiectasia gene [1].
• Several rodent studies have also suggested that intact 5-HT systems are important determinants of sensitivity and/or tolerance to ethanol-induced ataxia and hypothermia [2].
• Friedreich ataxia (FRDA), the most common autosomal recessive neurodegenerative disease among Europeans and people of European descent, is characterized by an early onset (usually before the age of 25), progressive ataxia, sensory loss, absence of tendon reflexes and pyramidal weakness of the legs [3].
• Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4 [4].
• We find no substantive defect in the p53 response of cells from ataxia telangiectasia or xeroderma pigmentosum complementation group A patients [5].

Psychiatry related information on Ataxia

• Ataxia-ocular apraxia 2 (AOA2) was recently identified as a new autosomal recessive ataxia [6].
• The most common symptoms before diagnosis were nonspecific: episodic extreme irritability (100 percent), episodic vomiting and lethargy (100 percent), protein avoidance (92 percent), ataxia (77 percent), Stage II coma (46 percent), delayed physical growth (38 percent), developmental delay (38 percent), and seizures (23 percent) [7].
• Joubert syndrome (JS) is an autosomal recessive disorder marked by agenesis of the cerebellar vermis, ataxia, hypotonia, oculomotor apraxia, neonatal breathing abnormalities, and mental retardation [8].
• GLUT-1+/- mice have epileptiform discharges on electroencephalography (EEG), impaired motor activity, incoordination, hypoglycorrhachia, microencephaly, decreased brain glucose uptake as measured by positron emission tomography (PET) scan and decreased brain Glut-1 expression by western blot (66%) [9].
• Within one-and-a-half years this deterioration led to severe dementia, autism, loss of purposeful use of the hands, jerky truncal ataxia, and acquired microcephaly [10].

High impact information on Ataxia

• Mutations in a novel gene encoding a CRAL-TRIO domain cause human Cayman ataxia and ataxia/dystonia in the jittery mouse [11].
• The newly recognized ataxia-ocular apraxia 1 (AOA1; MIM 208920) is the most frequent cause of autosomal recessive ataxia in Japan and is second only to Friedreich ataxia in Portugal [12].
• Mammalian Nova antigens (1 and 2) constitute an important family of regulators of RNA metabolism in neurons, first identified using sera from cancer patients with the autoimmune disorder paraneoplastic opsoclonus-myoclonus ataxia (POMA) [13].
• MEC1 is a homolog of ATM, mutations in which cause ataxia telangiectasia (A-T), a disease characterized by various neurologic and immunologic abnormalities, a predisposition for cancer, and a cellular defect in repair of DSBs [14].
• Consistent with the lack of p53 activation by IR in ataxia telangiectasia (AT; refs 14,15), neither Ser376 dephosphorylation, nor the interaction of p53 with 14-3-3 proteins occurred in AT cells [15].

Chemical compound and disease context of Ataxia

• Ataxia with isolated vitamin E deficiency is caused by mutations in the alpha-tocopherol transfer protein [16].
• We describe seven adults who had ataxia and severe sensory-nervous-system dysfunction after daily high-level pyridoxine (vitamin B6) consumption [17].
• Bleomycin-resistant DNA synthesis in ataxia telangiectasia cells [18].
• Accumulation of propidium iodide by Purkinje neurons of the vermis was associated with a reproducible behavioral abnormality characterized by truncal tremor, ataxia, and nystagmus [19].
• Partial agonists (such as imidazenil), which modestly amplify GABA action at many GABAA receptor subtypes, fail to cause tolerance, dependence, ataxia, or ethanol and barbiturate potentiation [20].

Biological context of Ataxia

• Cells from NBS patients are hypersensitive to ionizing radiation with cytogenetic features indistinguishable from ataxia telangiectasia [21].
• A gene, ATM, that is mutated in the autosomal recessive disorder ataxia telangiectasia (AT) was identified by positional cloning on chromosome 11q22-23 [22].
• We also provide evidence that BLM is phosphorylated after replication arrest in an Ataxia and RAD3-related protein (ATR)-dependent manner and that phosphorylation is not required for subnuclear relocalization [23].
• Catastrophic losses of telomeric sequences have recently been described during apoptosis, senescence and tumorigenesis in murine and human cells, in ataxia telangiectasia patients and in immortalized cells in which telomerase is inactive [24].
• The ataxia telangiectasia mutant (ATM) protein kinase regulates the cell's response to DNA damage through the phosphorylation of proteins involved in cell-cycle checkpoints and DNA repair [25].

Anatomical context of Ataxia

• The genetic basis of familial CLL is poorly understood, but recently germ line mutations in the Ataxia Telangiectasia (ATM) gene have been proposed to confer susceptibility to CLL [26].
• For these nine patients, neurological symptoms consisted of seizures, coma, brain stem symptoms, or ataxia [27].
• Friedreich Ataxia (FRDA), the most prevalent of the inherited ataxias, is a multi-systemic disease with loss of sensory neurons and life-threatening hypertrophic cardiomyopathy as its most severe manifestations [28].
• In this study, we report constitutively elevated levels of two IFN-beta-inducible proteins, ubiquitin cross-reactive protein (UCRP), and low molecular weight protein (LMP2), in human fibroblasts with the inherited disease ataxia telangiectasia (AT) [29].
• Human lymphoblastoid cell lines from normal individuals and from patients with ataxia telangiectasia were either proficient or deficient in their ability to repair the mutagenic DNA adduct O6-methylguanine that is induced by methylating carcinogens [30].

Gene context of Ataxia

• Rad3 is an inessential member of the 'lipid kinase' subclass of kinases which includes the ATM protein defective in ataxia telangiectasia patients [31].
• No patient without a family history of ataxia, or with a pure cerebellar or spastic syndrome, tested positive for SCA1, SCA2, or SCA3 [32].
• Fragile-X-associated tremor/ataxia syndrome (FXTAS) in females with the FMR1 premutation [33].
• The entire coding region of PRKCG was sequenced in an affected member of family AT08 and in a group of 39 unrelated patients with ataxia not attributable to trinucleotide expansions [34].
• Our data show that mutations in the PEX7 gene may result in a broad clinical spectrum ranging from severe rhizomelic chondrodysplasia punctata to relatively mild RD and that clinical diagnosis of conditions involving retinitis pigmentosa, ataxia, and polyneuropathy may require a full screen of peroxisomal functions [35].

Analytical, diagnostic and therapeutic context of Ataxia

• Acetazolamide-responsive episodic ataxia in an Italian family refines gene mapping on chromosome 19p13 [36].
• Affected (par/par) mice can be first recognized at approximately postnatal day (PN) 7 to 8 and are characterized by their smaller-than-normal body size, a progressive generalized muscle weakness, and lack of coordination [37].
• Comprehensive dose-response assessments demonstrated that acute i.v. injections of (+)-MK801 induced a behavioral neurotoxic syndrome comprised of head-weaving, ataxia, hyperlocomotion and myoclonic/clonic behaviors and associated with disruptions in normal EEG rhythms including paroxysmal EEG spike/wave complexes [38].
• SKF 525A pretreatment markedly prolonged ataxia, analgesia and agitation, in addition to significantly elevating brain and plasms ketamine levels subsequent to the initial 10 minutes following injection; thus hepatic metabolism appeared to play a prominent role in the termination of the posthypnotic effects of the drug [39].
• To quantify ataxia in a simple way four tests were developed and analysed, based on the neurological examination: a tapping test for the arms (test 1), another one for the legs (test 2), a quantified finger-to-nose test (test 3), and a modified Romberg test (test 4) [40].

References