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Early Diagnosis of TTR Amyloidosis by Use of Molecular Biology (ADDITION)

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ClinicalTrials.gov Identifier: NCT03373370
Recruitment Status : Recruiting
First Posted : December 14, 2017
Last Update Posted : April 24, 2019
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Brief Summary:

Peripheral neuropathies are diseases that affect the nervous system outside the brain and spinal cord, their prevalence is 1% in the general population, the causes are extremely varied with more than 200 identified causes; the main ones are diabetes, excessive alcohol consumption and chemotherapy. They may be sometimes disabling but generally preserve autonomy.

Transthyretin amyloidosis is a rare multisystematic hereditary disease with autosomal dominant transmission. They present usually as a peripheral neuropathies (FAP). They are due to a point mutation of the transthyretin gene (chr 18q). FAP is secondary to endoneurial amyloid deposits and are characterized by a slowly progressive sensory, motor and autonomic. FAP is the most severe hereditary polyneuropathy of the adult are irreversible and fatal within 5 to 12 years from onset.

Most frequent mutation of TTR gene is located on the second exon; but more than 100 mutations have been reported.

Prevalence of FAP is 1 per 1 million inhabitants. They have been reported until 1990s' in four endemic areas North of Portugal, Sweden, Japan and Majorca. In these areas, diagnosis is facilitated because of the stereotypical presentation : a length-dependent polyneuropathy with predominant involvement of thermal and pain sensations and autonomic dysfunction, early onset in the third decade and a predominant Met30 TTR mutation. Positive family history is frequent 85% (one of the parents is affected). Diagnosis requires detection of TTR mutation by molecular biology (blood sample) and characterization of amyloid deposit on labial salivary gland biopsy.


Condition or disease
Polyneuropathy Diagnosis Idiopathic Progressive Neuropathy

Detailed Description:

Study of the TTR gene by complete sequencing; search for amyloidogenic mutations of the TTR gene (according to the site http: // amyloidosismutations.com / mut-attr.php) in the laboratory of molecular biology of the CHU BICÊTRE (APHP) managed by Pr Anne Mantel.

Preselection of the cases to be tested among the cases of peripheral neuropathies of indetermined cause referred via the network Cornamyl of which the reference centers of the neuromuscular diseases are belonging .

Currently, FAP is a worldwide disease. Diagnosis of TTR-FAP is extremely difficult and usually delayed by 4 years in non endemic areas for many reasons :

  • positive family history are lacking in 50% of cases (sporadic forms).
  • incomplete ability of biopsies to characterize amyloid deposits.
  • clinical presentation is varied and may mimick many types of rare peripheral neuropathies: CIDP, axonal idiopathic polyneuropathy, upper limb neuropathies, recurrent carpal tunnel syndrome after surgery, ataxic neuropathy, motor neuropathy.

Conversely to endemic areas, look for V30M mutation is not enough to exclude TTR-FAP, TTR gene sequencing is required.

With the help of the french network for FAP (Cornamyl), cases have been identified in 81/100 geographical departments, with a wide genetic heterogeneity (41 mutations reported) ; age of onset is late: 75% after 50 yo.


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Study Type : Observational
Estimated Enrollment : 1000 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Project to Accelerate the Diagnosis of TTR Amyloidosis by Use of Molecular Biology in First Intention
Actual Study Start Date : March 17, 2017
Estimated Primary Completion Date : March 27, 2020
Estimated Study Completion Date : December 30, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Amyloidosis




Primary Outcome Measures :
  1. Rate of amyloidogenic TTR mutation [ Time Frame: 1 day ]
    Rate of amyloidogenic TTR mutation in progressive idiopathic polyneuropathy


Secondary Outcome Measures :
  1. To identify the rate of amyloidogenic TTR mutation in different subgroups of patients with neuropathy [ Time Frame: 1 day ]
    Rate of amyloidogenic TTR mutation in different subgroups of patients with neuropathy : disabling neuropathy (including ataxic).

  2. To identify the rate of amyloidogenic TTR mutation in different subgroups of patients with neuropathy :variant Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) [ Time Frame: 1 day ]
    Rate of amyloidogenic TTR mutation in different subgroups of patients with neuropathy :variant Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)

  3. To identify the rate of amyloidogenic TTR mutation in different subgroups of patients with neuropathy : upper limb onset neuropathy. [ Time Frame: 1 day ]
    Rate of amyloidogenic TTR mutation in different subgroups of patients with neuropathy : upper limb onset neuropathy.



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Ages Eligible for Study:   51 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Sampling Method:   Non-Probability Sample
Study Population
Multicentric prospective population in tertiary referal center for neuromuscular diseases
Criteria

Inclusion Criteria:

  • A. Adult (>50 yo)
  • Chronic Peripheral neuropathies (progressing since 12 months),
  • Peripheral neuropathies documentated by ENMG.

    1. Chronic polyneuropathy with dysautonomia (orthostatic hypotension) without diabetes
    2. Atypical CIDP (situations C, D (even with high protid content on CSF) & E as defined by the French group for study of CIDP).
    3. Disabling neuropathy (gait or balance disorder)
    4. Neuropathies with upper limb onset who underwent previously CTS surgery without success.
    5. SLA-like syndrome : areflexia with sensory alterations on ENMG. 6: Deterioration of SNAPs' amplitudes on NCS > 30% in less than6 months by the same NCS laboratory Mandatory : A+B+C one of 1 to 6

Exclusion criteria :

  • Amyloid deposit characterized on biopsy
  • Causes of chronic polyneuropathy : Diabetes mellitus, Chronic alcoholic intoxication
  • CIDP responding to IVIg or corticosteroids (improvement by 1 point of ONLS).
  • Neuropathy associated with monoclonal gammapathy and i) anti-MAG activity or ii) POEMS syndrome or) CANOMAD syndrome.
  • Ataxic Neuropathy due to vitamine B12 deficiency
  • Ataxic Neuropathy due to IgM anti-MAG,
  • CANOMAD syndrome,
  • Ganglionopathy by Sjögren's syndrome, or paraneoplastic syndrome with Anti- Hu Antibodies, chemotherapy induced (cis-platine, oxaliplatine).
  • Positive family history of FAP or FAC
  • Proven AL amyloidosis

Exclusion Criteria:

-


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03373370


Contacts
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Contact: David ADAMS 01 45 21 27 11 david.adams@aphp.fr
Contact: Céline LABEYRIE 0145213159 celine.labeyrie@aphp.fr

Locations
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France
Chu Bicetre Recruiting
Le Kremlin Bicetre, Kremlin Bicetre, France, 94270
Contact: David ADAMS    01 45 21 27 11    david.adams@aphp.fr   
Contact: Céline LABEYRIE    0145213159    celine.labeyrie@aphp.fr   
CHU Martinique Active, not recruiting
Martigues, Martinique, France, 97200
CHU Saint Etienne Recruiting
Saint-Étienne, Saint Etienne, France
Contact: ANTOINE Jean-Christophe    00(33) 4 77 12 78 05    j.christophe.antoine@chu-st-etienne.fr   
CHU Grenoble Recruiting
Grenoble, France, 38043
Contact: Emmeline Lagrange    04 76 76 61 61    elagrange@grenoble.fr   
CHRU Lille Recruiting
Lille, France, 59037
Contact: Céline TARD    00 (33) 320445962    celine.tard@chru-lille.fr   
CHU Dupuytren Recruiting
Limoges, France, 87042
Contact: Laurent MAGY    05 55 05 65 61    laurent.magy@unilim.fr   
CHU La Timone Recruiting
Marseille, France, 13000
Contact: Shahram ATTARIAN    04 91 38 65 79    sattarian@ap-hm.fr   
Hopital guy-de-Chauliac Recruiting
Montpellier, France, 34295
Contact: RAUL JUNTAS MORALES    04 67 33 78 22    r-juntasmorales@chu-montpellier.fr   
Hôpital de La Salpetrière Recruiting
Paris, France, 75013
Contact: VIALA Karine    0142161945    karine.viala@aphp.fr   
Hopital de Hautepierre Recruiting
Strasbourg, France, 67098
Contact: ANDONI ECHANIZ-LAGUNA    03 88 12 85 59    andoni.echaniz-laguna@chru-strasbourg.fr   
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Investigators
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Principal Investigator: David ADAMS Bicetre Hospital

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Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT03373370     History of Changes
Other Study ID Numbers: NI 16007
First Posted: December 14, 2017    Key Record Dates
Last Update Posted: April 24, 2019
Last Verified: April 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Polyneuropathies
Amyloidosis
Proteostasis Deficiencies
Metabolic Diseases
Peripheral Nervous System Diseases
Neuromuscular Diseases
Nervous System Diseases