Early Diagnosis of TTR Amyloidosis by Use of Molecular Biology

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    Assistance Publique - Hôpitaux de Paris
Updated on 9 July 2020
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CHU Dupuytren (0.0 mi away) Contact
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early detection
autosomal dominant
spinal cord
hereditary disease


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.


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 BICTRE (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.

Clinical Study IdentifierNCT03373370
SponsorAssistance Publique - Hôpitaux de Paris
Last Modified on9 July 2020

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Inclusion Criteria

Is your age greater than or equal to 51 yrs?
Gender: Male or Female
Do you have any of these conditions: Peripheral Neuropathy or Differential diagnostic aspects or Polyneuropathy or Idiopathic Progressive Neuropathy or Diagnosis?
A. Adult (>50 yo)
Chronic Peripheral neuropathies (progressing since 12 months)
Peripheral neuropathies documentated by ENMG
Chronic polyneuropathy with dysautonomia (orthostatic hypotension) without diabetes
Atypical CIDP (situations C, D (even with high protid content on CSF) & E as defined by the French group for study of CIDP)
Disabling neuropathy (gait or balance disorder)
Neuropathies with upper limb onset who underwent previously CTS surgery without success
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 Sjgren'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
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