Motor System Genomics

We are studying biological fluid samples from MND patients, family members of the patients with MND, disease control (patients with other motor system disorders and neurological conditions) and healthy controls to identify markers that could be used to aid diagnosis. We hope that particular changes in fluid composition may help us to understand how MND arises, how to diagnose the condition at an earlier stage and to understand responses to treatment. We currently study two fluids and skin cells as detailed below:
Cerebrospinal Fluid (CSF)
Cerebrospinal fluid is the liquid that surrounds the brain and spinal cord. We are studying changes in the composition to help understand the biochemical changes happening in MND.
Blood has the advantage of being an easily accessible fluid to examine. The aim of this project is to identify MND specific, blood-based biological ‘fingerprints’ that can be useful in diagnosis, prognosis prediction and disease monitoring.
The skin biopsy samples collected is for establishing cultured fibroblasts as an experimental model of disease. Skin samples are processed and the skin cells cultured in the lab to generate the fibroblasts.

Study titleGenetic and Transcriptomics Analysis of Motor System Disorders
UK Chief InvestigatorProfessor Dame Pamela Shaw
Research summaryMotor system disorders comprise of a variety of different disorders characterised by the inability of the cells in the nervous system to send signals to the muscles to control movement. These disorders include diseases where the motor neurones are degenerating eg motor neurone disease (MND) and hereditary spastic paraparesis (HSP) but similar clinical symptoms can also be caused by inflammatory or non-inflammatory neuropathies and structural defects in the spinal cord. Clinical diagnosis of MND and HSP are through exclusion of other potential causes rather than a single test. The majority of cases of MND and HSP are usually sporadic with no family history of the disease. However inheritance of the disease in a family can occur and the genetic basis of these cases is being elucidated, identifying mutations in causative genes not only in familial cases but also in apparently sporadic cases raising the probability that some mutations are not fully penetrant ie carrying the mutation doesn’t always mean you will get the disease. There are still causative genes to be identified. Determining the genetic basis of diseases allows for questions to be raised. How does this gene cause the disease? Can pathways affected by the mutation be corrected by therapeutic intervention? Does this genetic variant of disease have a characteristic clinical phenotype which can be used to aid diagnosis or inform prognosis of other cases? Can we distinguish this variant of disease by looking at blood samples? The primary aim of this project is to determine how particular gene mutations cause a wide range of motor system disorders and to establish if expression of a set of genes can be used as a biomarker. We will collect blood, skin and CSF samples (patients, family members & healthy controls) to isolate DNA, RNA, proteins & metabolites and use the cells to establish cellular models to identify new genes, determine the mechanisms of disease, establish diagnostic & prognostic biomarkers.
Inclusion/exclusion criteriaINCLUSION CRITERIA
All participants must:
• Be able and willing to participate in the study and provide informed consent. If the participant is unable to provide written consent, an independent witness will be present at the informed consent discussion and sign the consent form on the participant’s behalf.
• Be at least 18 years old.

In addition to the general inclusion/exclusion criteria described above, the additional eligibility criteria apply:
• Participants with liver disease or bleeding disorders will require review and confirmation from a clinician prior to undergoing the skin biopsy procedure.
• CSF samples will only be taken from patients who are undergoing a lumbar puncture for clinical reasons.

Potential participants will not be admitted to the study if they:
• Do not have capacity to consent for any reason.
• Are under the age of 18.
Current statusActive – recruiting
Contact detailsMbombe Kazoka, email: or phone: 0114 222 2258.
Lee Tuddenham, email: or phone: 0114 222 2263.
Recruitment group(s)Participant groups:
1. Patients with motor system disorders;
2. Patients with other neurological conditions (disease controls);
3. Family members of patients;
4. Neurologically healthy volunteers.
Recruitment target(s)The study aims to recruit up to 200 patients with motor system disorders, 100 patients with other neurological conditions (disease controls), 200 family members and 100 healthy controls per year for a duration of ten years. The maximum number of participants recruited into the study will be 6,000, minimum of 2000.
Key datesActual opening date: 08 August 2012
Recruitment planned end date: 30 September 2022
Funder(s)Medical Research Council (MRC)
SponsorSheffield Teaching Hospitals NHS Foundation Trust
Study designCohort observational
Intervention (if applicable)Not applicable
Phase (if applicable)Not applicable
Outcome measuresBlood, CSF, skin, and urine samples, and supporting clinical and genetic data from patients with motor system disorders, those with other neurological disorders, family members and healthy volunteers.
Publications / Results reportsLinks will be provided when papers are published.
Participant Information SheetInformation Sheet - Patients, v1-0, 06Jun2012
Information Sheet - Family members & controls, v1-0, 06Jun2012