ABSTRACT
Ataxia-telangiectasia (A-T) is an autosomal recessive neurodegenerative disorder with multisystem involvement and cancer predisposition, caused by mutations in the A-T mutated (ATM) gene. To study genotype-phenotype correlations, we evaluated the clinical and laboratory data of 51 genetically proven A-T patients, and additionally measured ATM protein expression and kinase activity. Patients without ATM kinase activity showed the classical phenotype. The presence of ATM protein, correlated with slightly better immunological function. Residual kinase activity correlated with a milder and essentially different neurological phenotype, absence of telangiectasia, normal endocrine and pulmonary function, normal immunoglobulins, significantly lower X-ray hypersensitivity in lymphocytes, and extended lifespan. In these patients, cancer occurred later in life and generally consisted of solid instead of lymphoid malignancies. The genotypes of severely affected patients generally included truncating mutations resulting in total absence of ATM kinase activity, while patients with milder phenotypes harbored at least one missense or splice site mutation resulting in expression of ATM with some kinase activity. Overall, the phenotypic manifestations in A-T show a continuous spectrum from severe classical childhood-onset A-T to a relatively mild adult-onset disorder, depending on the presence of ATM protein and kinase activity. Each patient is left with a tremendously increased cancer risk.
Subject(s)
Ataxia Telangiectasia/metabolism , Ataxia Telangiectasia/pathology , Cell Cycle Proteins/metabolism , DNA-Binding Proteins/metabolism , Protein Serine-Threonine Kinases/metabolism , Tumor Suppressor Proteins/metabolism , Adolescent , Adult , Ataxia Telangiectasia/genetics , Ataxia Telangiectasia Mutated Proteins , Cell Cycle Proteins/genetics , Child , DNA-Binding Proteins/genetics , Female , Genetic Association Studies , Humans , Male , Middle Aged , Protein Serine-Threonine Kinases/genetics , Tumor Suppressor Proteins/genetics , Young AdultABSTRACT
Observational studies of up to 12 months duration showed that glatiramer acetate (GA) treatment of relapsing-remitting multiple sclerosis may result in decreased fatigue and improves health-related quality of life (HRQoL), with no changes in disability or mood. We investigated whether in the second year of treatment these improvements are sustained, disability or mood yet improved, and 2-year changes may be predicted by changes in the first 6 or 12 months. The multi-center FOCUS-Extension study was a prospective extension of the 12-month, international, observational FOCUS study and included 67 patients (38 treatment-naïve, 29 pre-treated) of the Dutch FOCUS cohort. Fatigue, HRQoL, depression and disability were measured by the Fatigue Impact Scale (FIS), Leeds Multiple Sclerosis Quality of Life (LMSQoL) questionnaire, Beck Depression Inventory-Short Form and the Guy's Neurological Disability Scale. A 2-year period of GA treatment was associated with -0.52 and +0.66 standard deviation changes in mean FIS and LMSQoL scores compared to baseline, whereas disability and mood remained unchanged. For FIS and LMSQoL, the Pearson correlation coefficients between 6-month changes and 2-year scores were 0.47 and 0.50, and between 12-month changes and 2-year scores 0.65 and 0.62. After 2 years GA treatment, the improvements in fatigue and HRQoL observed at 1 year are sustained, whereas disability and mood remain unchanged compared to baseline. Moreover, the levels of fatigue and HRQoL at 2 years GA treatment are predicted by the improvements at 6 months.