RARE DISEASES

Rare diseases such as Huntington's disease, dystonia and Tourette syndrome are part of the ICM research objectives.
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DISEASE DESCRIPTION

Several teams of the ICM are acting together to fight movement and rare neurological diseases, such as Huntington’s disease, cerebellar ataxias, spastic paraparesis, Child alternating hemiplegia, autoimmune forms of neuropathy, congenital myasthenic syndromes and neuromuscular channelopathies.

Over 6000 rare diseases are characterised by a great diversity of disorders and symptoms that vary not only from one disease to another but also between patients with the same disease.

Rare diseases have many causes (genetic, infectious, neuromuscular…), and 65% of these diseases are serious and disabling.

ICM RESPONSES

TOPICS AND RESEARCH TEAMS

  • Treat Huntington’s disease by improving brain metabolism with Alexis Brice’s team.
  • Identify genes responsible for cerebellar ataxias and hereditary spastic paraplegias, and understand the mechanisms involved to develop treatments with Alexis Brice’s team.
  • Understand movement diseases (dystonia, mirror movement syndrome, Tourette syndrome, tremor) to find new therapeutic leads with Marie Vidailhet and Stéphane Lehéricy’s team.
  • Better diagnose and understand neuromuscular excitability diseases, such as muscular channelopathies, myasthenia and chronic inflammatory demyelinating polyneuropathy, to improve patient management with Laure Strochlic in Bertrand Fontaine and Sophie Nicole’s team.

HIGHLIGHTS

Cerebellar ataxias : towards treatment identification ?

Cerebellar ataxias are neurological disorders affecting the cerebellum, major structure of the central nervous system, involved in balance and coordination. Patients with this disease show symptoms of walking disorders or are unable to achieve precise movements. Giovanni Stevanin in Alexis Brice’s team has identified a recurrent mutation in a new gene responsible for cerebellar ataxia, coding for a calcium channel expressed in some cerebellum neurons. Many drugs regulating calcium channel activity are widely used and this discovery could lead to therapeutic advances for these rare diseases.

Hereditary spastic paraparesis : discovery of a new mechanism

Hereditary spastic paraplegias are a heterogeneous group of diseases on a clinical and genetic level. These neurodegenerative disorders affect people of all ages. Clinical signs gradually settle down and are characterised by crippling walking disorders caused by lower limb stiffness (spasticity). Giovanni Stevanin and his collaborators within Alexis Brice’s team, have highlighted that mutations within the same gene, ALDH18A1, are associated with several types of hereditary spastic paraplegias and to different transmission modes. Moreover, researchers have identified a new blood marker associated with the disease, which would enable its diagnosis. These results contribute to a better understanding of the disease and a more accurate diagnosis.

Tourette syndrome : are tics a bad habit ?

Tics are the main expression of Tourette syndrome. How do they appear ? Why do they persist ? Yulia Worbe, in Mary Vidailhet’s team, and her colleagues, have shown that patients with Tourette syndrome develop more habitual behaviours than healthy subjects of the same age. These results provide new insights on the mechanisms at the basis of the formation and persistence of tics, which may be, in part, learned actions becoming automatic, and persistent in the same way as bad habits. Degradations of some neural networks involved in the genesis of habits and increased dopamine transmission (neurotransmitter involved in reward citcuits) could explain the exacerbation of these habitual behaviours in patients. These results allow the development of new therapeutic approaches to fight Tourette syndrome.

Channelopathies and myasthenic congenital syndromes : a new mutation in question

Muscular channelopathies constitute another heterogeneous group of genetic diseases which have in common to be caused by gene mutations encoding for ion channels critical for muscle contraction and relaxation. For the first time, Sophie Nicole and her collaborators in Bertrand Fontaine’s team have identified a recessive mutation in a sodium channel responsible for permanent muscle weakness, characteristic of myasthenic congenital syndrome associated with periodic paralysis. This discovery will help refining the diagnosis of these two groups of heterogeneous genetic diseases and opens research directions for therapeutic molecules capable of boosting sodium channel functioning as remedies to an initial permanent muscular weakness.

CLINICAL RESEARCH

A drug to treat dystonia

A study coordinated by Emmanuel Flamand-Roze has tested the efficiency of zonisamide, a drug now used to treat some forms of epilepsy, among 23 patients with a rare disease of the nervous system, myoclonic dystonia. The very promising results of this trial show that zonisamide significantly reduces myoclonia and the related disability. Dystonia, abnormal posture of some patient body parts is also improved by this treatment.

Effect of a drug on myotonias

Non-dystrophic myotonias are rare diseases due to muscle ion channel genetic mutations leading to channel function loss. It is clinically manifested by muscle relaxation difficulty, causing painful stiffness. The first controlled experiment conducted by Bertrand Fontaine and Savine Vicart, aimed to assess the efficacy and safety of Mexiletine in this disease, has just been completed. The very encouraging results are currently being analysed.

Resveratrol to fight Huntington’s disease

Huntington’s disease is a hereditary neurodegenerative condition manifested by the appearance of motor, behavioural and psychiatric progressive disorders. A phase II national multicentric trial, REV-HD, coordinated by Fanny Mochel, was initiated in 2015 in order to assess resveratrol abilities to slow down Huntington’s disease progression by improving brain energetic functioning. A hundred patients will be treated for one year with clinical and imaging parameters as evaluation criteria.

An oil medicine to treat abnormal movements of metabolic origin

Fanny MOCHEL’s team, in collaboration with Emmanuel Flamand-Roze, has tested the effectiveness of triheptanoïne, an oil medicine in patients with a deficit in GLUT-1 (Glucose transporter 1), characterised by cognitive and motor impairments, including involuntary abnormal movement transitional crises. This treatment reduces the onset of symptoms in children and adult patients by 90% in restoring the energetic metabolism in the brain. Following these results, a phase 3 international multicentric study, in collaboration with the Ultragenyx company, will be initiated by the end of 2016.

RESEARCH DEVELOPMENT

An oil medicine to treat Huntington’s disease

The therapeutic potential of a synthetic oil, triheptanoïne, has been demonstrated by Fanny Mochel and Alexandra Durr in Alexis Brice’s team in patients with Huntington’s disease. By improving brain energetic functioning, this medicine may slow the progression of the disease. On the basis of these results, a European therapeutic trial, TRIHEP3, coordinated by Fanny Mochel and conducted in partnership with Ultragenyx, was initiated in France and the Netherlands, for a period of one year in a hundred patients with clinical and imaging parameters as assessment criteria.