Biomarker Research in Inherited Movement Disorders

Inherited movement disorders are rare conditions, whose cumulative prevalence are in the order of 5-10/100,000 inhabitants, in most cases progressive and can lead to a significant loss of autonomy after one or more decades of evolution. They include spinocerebellar ataxias and hyperkinetic disorders (dystonias, choreas, tremor, parkinsonism and myoclonus with variable combination of those, or more complex alteration of movements). The existence of the National Reference Centre (CMR) for Rare Diseases (CMR Neurogenetics, devoted to ataxias and spastic paraparesis, dystonia and rare movement disorders and CMR Huntington, devoted to Huntington Disease) has allowed a more integrated vision of these diseases. This is illustrated, in the same family, by the occurrence of different clinical expressions of spinocerebellar ataxias and hyperkinetic disorders that share the same genetic background. Conversely, different causal mutations within the same gene may have very different ages at onset and a wide range of clinical expression, and the spectrum of new phenotypes linked to a single gene is still expanding .

any ataxia and dystonia genes are involved in similar pathways. There are numerous arguments supporting a share pathogenesis including synaptic transmission and neurodevelopment .

Overall, there are a number of arguments for a shared genetic approach and biomarkers research for these inherited movement disorders:

• Evidence from a clinico-genetic approach: A combination of several movement disorders is often observed in the same patient with causative mutation in either genetic groups of spinocerebellar degenerations, dystonias or choreas.
• Evidence from neuroimaging: the current concept of networks disorders underlies the pathophysiology of these hyperkinetic movement disorders. Variable combination of functional and/ or structural alterations of the cerebello-thalamo-cortical, cortex-basal ganglia and corticospinal networks, and their complex interactions have been described in ataxias ,dystonia choreas and more complex disorders.
• Genetic diagnosis: deciphering diagnosis with wide range of phenotypes Even in times of next generation sequencing covering exomes and genomes, diagnosing spinocerebellar degenerations, dystonia and other hyperkinetic disorders remains a challenge as: i) the causative gene remains to be identified for a substantial share those disorders; the pathogenicity of variants of unknown significance in known and potential novel disease genes often requires time-consuming functional analyses not available on a routine basis; ii) in many countries, including France, access to diagnostic whole exome and whole genome sequencing is still limited; iii) the proportions of abnormal expansions not seen in exome studies are frequent in spinocerebellar degenerations and need a technological development to identify them. Analysis of familial forms revealed a great heterogeneity of the phenotype within the same family in terms of age at onset, severity and clinical presentation. Moreover, this phenotypic variability is not explained only by the genetic heterogeneity but also by the underlying frequent exonic or intronic expansions of triplet or more complex repeats, and more recently by the discovery of genetic modifiers ; iv) for dystonia and hyperkinetic disorders, some of those disorders also include nonmovement disorders neurological (e.g. intellectual deficiencies, hypotonia at birth, immature motor control, deafness, visual defects) and non-neurological (dysmorphological features) symptoms and the movement disorders panels do not always include the genes involved in developmental disorders; v) among the dominantly inherited forms such as Huntington disease, the access to genetic testing procedures allows early preventive therapeutic interventions in premanifest individuals. There is a lack of clinical evaluation to tackle the efficiency of treatment and the need for biomarker development.
• Natural history and prognosis: need for quantitative, reproducible markers, sensitive to evolution Biomarkers search is ongoing in those pathologies. They are valuable in assisting diagnosis, have prognostic value, quantify disease progression and serve as outcome parameters in clinical trials.

These elements demonstrate the need to develop quantitative tools that are easy to use, reproducible and sensitive to disease progression in order to accurately determine the natural history of the disease. This lack of systematic knowledge impedes diagnosis, patient counselling and therapy development.

Overall: Identification of the underlying gene and its pathogenic changes or variant(s) contributes to precise diagnosis, genetic counselling and follow-up. Advances in molecular genetics have highlighted the genotypic complexity, justifying the need for rigorous clinical and para-clinical evaluation to establish relevant phenotype-genotype correlations. In dystonia and in spinocerebellar degenerations attempts have been made to classify the genes involved.

Molecular genetic analysis will make it possible to specify the correlations between phenotype and genotype in order to propose rational molecular diagnostic strategies based on the frequency and nature of mutations, taking into account the phenotype. Genetic analyses will have an impact in terms of public health since they will serve as a basis for guiding requests for molecular analyses in these pathologies. In addition, recent advances in therapeutic trials will need the careful selection of participants, mostly based on biomarkers, for successful testing of new therapeutical agents. Therefore, it seems essential that this cohort of patients be supplemented by a collection of biological material for genetic research.

BIOMOV project aims to : 1) establish the clinical spectrum and natural history of these diseases, 2) understand the role of genetic and familial factors on the phenotype, 3) elucidate the molecular basis of these disorders and evaluate diagnostic strategies involving molecular tools for clinical and genetic management, 4) develop multimodal biomarkers both for physiopathological studies and for accurate measures of disease progression, 5) develop trial ready cohorts of well characterized genetic patients, 6) test new therapies either symptomatic or based on pathophysiological mechanisms.

It is crucial to be able to establish a large cohort of patients whose genotype will be specified. Follow-up of patients at different stages of the disease will make it possible to collect the natural history of the disease in a descriptive manner, with prospects for patient management, since the prognosis in terms of loss of autonomy or disability will be better specified. However, the main interest of the proposed clinical follow-up is to be able to quantitatively describe the progression of the main neurological diseases. These data are absolutely essential for the future implementation of therapeutic trials. The number of patients likely to be recruited and followed up a unique resource for such a project