Ataxia telangiectasia (A-T) is a rare devastating human recessive disorder characterized by progressive cerebellar ataxia, immunodeficiency, chromosomal instability, and cancer susceptibility. The underlying mechanism and process of neurodegeneration leading to loss of cerebellar neurons and neurological function is largely unknown. Laboratory diagnostic approaches to neurodegeneration in A-T are hampered by sampling issues. It is dangerous, impractical, and not ethically to directly sample brain tissue by surgical biopsy. In contrast cerebrospinal fluid (CSF), a fluid that is in direct contact with brain tissue, is relatively easy to sample in a safe procedure (lumbar puncture). The aim of the proposal is to investigate oxidative stress, low grade inflammation and tissue break down in the brain of A-T patients by analyzing CSF. In addition the alterations in protein expression related to A-T will be quantified by liquid chromatography/mass spectrometry (LC/MS)-based proteomic analysis of CSF from healthy individuals and A-T patients to determine candidate proteins (new biomarkers) which relative expression levels could be used as surrogate marker of disease progression.

Ataxia telangiectasia (A-T) is a devastating human recessive disorder characterized by progressive cerebellar ataxia, immunodeficiency, chromosomal instability, and cancer susceptibility. For clinicians and scientists the underlying mechanism and process of neurodegeneration leading to loss of cerebellar neurons and neurological function is largely unknown. In addition no surrogate marker of neurological degeneration and disease progression exist.

Three major factors may be responsible for progression of neurodegeneration:

1. A-T patients exhibit elevated levels of reactive oxygen species (ROS) and reduced anti-oxidative capacity. It has been proposed that ROS is responsible for destruction of the purkinje cells in the cerebellum.
2. Ongoing low grade inflammation due to immunodeficiency. Elevated serum interleukin-8 (IL-8) levels in patients with A-T are postulated that systemic inflammation may contribute to the disease phenotype. How inflammation and neurodegeneration interact is, however, a matter of ongoing debate.
3. Low levels of growth hormones (GH). Extracerebellar MRI - lesions in A-T go along with deficiency of the GH axis, high Ataxia scores and advanced age.

The aim of the proposal is to investigate oxidative stress, low grade inflammation, tissue breakdown and biomarkers in cerebrospinal fluid (CSF), a fluid that is in direct contact with central nervous system (CNS), of A-T patients.

• To analyse functional gene expression of oxidative stress and low grade inflammation by means of reverse transcriptase-polymerase chain reaction (RT-PCR) and cytometric bead array.
• To characterize the alterations in protein expression related to A-T, a LC/MS-based quantitative proteomic analysis of CSF from control and A-T patients
• To compare alterations in protein expression levels in CSF with MRI findings in different age groups of classical A-T.
• To determine candidate proteins whose relative expression levels could be used as surrogate marker of disease progression?
• To established an analysis system on a basis of multiplex ELISA-technique to evaluate potential candidates/surrogate markers for disease progression in a larger cohort of patients.

Inclusion Criteria:

• Aim group: clinically and/or genetically diagnosed Ataxia telangiectasia; Control group: neurologic non-inflammatory disease with an indication for diagnostic or therapeutic lumbar puncture
• age between 2 and 40 years
• written informed consent

Exclusion Criteria:

• fever or clinical signs of an infection
• leucocyte count >12´000/µl and C reactive protein (CrP) >2mg/dl
• chronic diseases with need of immunomodulatory therapies (bronchial asthma, rheumatoid arthritis)
• medication with statins
• other diseases with influence in the immunosystem (i.e. diabetes mellitus, malignoma, renal failure requiring dialysis)