Curr Neurol Neurosci Rep (2014) 14:435 DOI 10.1007/s11910-013-0435-3
NERVE AND MUSCLE (L WEIMER, SECTION EDITOR)
FAP Neuropathy and Emerging Treatments David Adams & Marie Théaudin & Cecile Cauquil & Vincent Algalarrondo & Michel Slama
# Springer Science+Business Media New York 2014
Abstract Transthyretin familial amyloid polyneuropathy (TTR-FAP) classically presents as a length dependent small fiber polyneuropathy in endemic countries like Portugal. In nonendemic countries, it may mimic a variety of chronic polyneuropathies, with several phenotypes: ataxic, upper limb onset neuropathy, or motor. In these cases, there is usually a late onset and no positive family history. TTR gene sequencing appears the most pertinent first-line test for diagnosis. Cardiac involvement of various severities is common in FAP. Liver transplantation remains the standard antiamyloid therapy with better results in Val30Met TTR-FAP of early onset. Antiamyloid medication has been developed. (1) TTR stabilizers: Tafamidis was the first drug approved in Europe in stage 1 (walking unaided) TTR-FAP to slow progression of the disease; diflunisal has been assessed in a phase 3 clinical trial; (2) TTR gene silencing is a new strategy to inhibit production of both mutant and nonmutant TTR with antisense oligonucleotides or SiRNA (2 ongoing phase 3 clinical trials). Keywords Familial amyloid polyneuropathy . Transthyretin . Nonmutant . Mutant . Mutations . Late onset . Sporadic . This article is part of the Topical Collection on Nerve and Muscle D. Adams : M. Théaudin : C. Cauquil : V. Algalarrondo : M. Slama APHP, HUPS, Univ Paris Sud, le Kremlin Bicêtre Cedex, France D. Adams (*) : M. Théaudin : C. Cauquil Department of Neurology, CHU Bicêtre, 78 rue du général leclerc, 94275 le Kremlin Bicêtre Cedex, France e-mail: [email protected] V. Algalarrondo Department of Cardiology (NNERf), CHU Antoine Beclere, Clamart, France D. Adams : M. Théaudin : V. Algalarrondo : M. Slama Inserm U788, French Referral Center for Familial Amyloid Polyneuropathy (NNERf), Paris, France
Diagnosis . Nerve biopsy . Labial salivary gland biopsy . TTR gene analysis . Liver transplantation . Tafamidis . RNAi therapy . Antisense oligonucleotide . Genetic counseling . Anticipation . Diagnosis . Heterogeneity . Pacemaker . Domino liver transplantation
Introduction Transthyretin familial amyloid polyneuropathy (TTR-FAP) is a rare systemic disease due to endoneurial amyloid deposit [1]. TTR-FAP is the most severe and disabling hereditary peripheral neuropathy occurring in adults. It is an autosomal transmission disease due to a point mutation of the TTR gene. The most common presentation is that of a length dependent peripheral and autonomic neuropathy with predominantly small fiber involvement associated with cardiomyopathy and significant weight loss. The disease is progressive, irreversible, disabling, leading to progressive disability. It is also lifethreatening; patients may die from cachexia, severe infection, or sudden death within 12 years from onset [2]. Overall prevalence of TTR-FAP is estimated to be 0.87–1.1 per 1, 000, 000 persons [3]. TTR-FAP has long been considered an endemic disease in north Portugal [4], Japan [3], and Sweden [5] reaching 9×10-6 (1:909 inhabitants) to 11–15.5× 10-6 (1:1108 inhabitants) in Nagano prefecture [3], Skelleftea in Sweden [5], and district of Povoa or Vila do Conde in Portugal [4]. Early onset is usual in Portugal and Japan (87 % of patients developing symptoms before 40 years of age) [4] whereas a late onset (87 % developing symptoms after 40 years of age) is classic in Sweden [5]. In the last 20 years, sporadic cases have been reported in Europe initially in France and UK, with a variety of TTR gene mutations including Val30Met [6]. Among Val30Met TTRFAP, late onset cases differ from early-onset cases by impairment of both superficial and deep sensory fibers with rare and
435, Page 2 of 12
mild autonomic symptoms, male predominance, and inconstant positive family history (50 %) [7, 8]. Concerning therapy, liver transplantation (LT), initially proposed 20 years ago as a treatment of TTR–FAP, suppresses the main source of variant TTR [9] and may stop disease progression. As of now, more than 2000 patients underwent LT in the world [10•]. Major and constant progress has been achieved in TTR-FAP in the last decades. In this review, we will focus on new and interesting findings in the spectrum of the disease, in therapy and therapeutic perspectives.
FAP Neuropathies Are Ubiquitous TTR-FAP is becoming clearly a world-wide disease often appearing to be a sporadic disease. TTR-FAP patients has been diagnosed in many continents; more recently in European countries such as Italy [11, 12•, 13], and Germany [14•], in North America including USA [15•] and central America [16, 17], and in Asia [18–20]. The incidence of TTR-FAP in national reference centers for FAP or amyloidosis is low but varies from 1 new case every 2 years [14•] to 20 new cases/ year [21•] (Table 1).
Curr Neurol Neurosci Rep (2014) 14:435
Biopsy for Diagnosis of TTR-FAP Biopsy is required in diagnosis of amyloidosis, in order to identify typical amyloid deposits by Congo red staining that demonstrates apple-green birefringence under cross-polarized light. However, sensitivity of biopsies is incomplete and the absence of amyloid deposit finding does not exclude the diagnosis; multiple biopsies can be necessary in some patients to reach the diagnosis. The sensitivity is low in abdominal fat ranging from 20 %–37 % [11, 12•], higher in labial salivary gland biopsy (LSGB) varying from 64 % [21•] to 91 % [23], and nerve biopsy ranging from 55 % [12•, 18] to 80 %–92 % [11, 14•, 21•]. Sensitivity varies widely from 1 center to another depending on experience and technique. TTR Gene Analysis Among the 100 TTR gene mutations, a majority are amyloidogenic, but some are only polymorphisms [24]. TTR gene analysis is largely used as a diagnostic tool in endemic countries looking for Val30Met variant, more rarely in nonendemic countries, where TTR gene sequencing allows identification of new mutations [14•, 25, 26, 27•] among patients with pathologically proven amyloid neuropathy.
Genetic Heterogeneity in TTR-FAP Val30Met is the most frequent genotype in the world and is by far the main mutation in Portugal and Sweden; however, the incidence differs considerably between countries. This mutation is not described in Mexico [16] or Taiwan [20] and approaches 50 % of cases in France [21•]. There is increasing genetic heterogeneity in many countries including 19 variants in Japan [22], 20 in Italy [13], 29 in France [21•], and 34 in the USA [15•] (Table 1).
Diagnosis of TTR-FAP Diagnosis of TTR-FAP remains difficult and requires expertise and adequate diagnostic methods. The delay between the first clinical signs and diagnosis varies from 2–6 years (Table 1). Main reasons are: absence of family history, atypical clinical presentations (varied phenotypes), inconstant autonomic dysfunction, difficulties to detect amyloid deposits in a single tissue biopsy, and rare use of TTR gene analysis in the screening of idiopathic polyneuropathy. Tools for Diagnosis Adequate diagnostic tools include biopsy to detect amyloid deposits and TTR gene sequencing to identify an amyloidogenic TTR gene mutation.
Spectrum of Phenotypes in TTR-FAP In endemic areas, TTR-FAP has a stereotypical presentation as a length dependent small fiber polyneuropathy mimicking diabetic polyneuropathy or as an inaugural autonomic neuropathy with digestive disorders or impotence, in association with weight loss [2]. In late onset Val30Met TTR-FAP (>50 years), both superficial and deep sensation are impaired with inconstant mild autonomic symptoms [8]. Many new clinical phenotypes have been recently identified, usually initially misleading diagnosis. Ataxic Phenotype An ataxic phenotype was recently reported in France in up to 26 % of TTR-FAP [21•] and in Germany [14•], usually with a non Met30TTR variant [14•, 21•]. Initial neuropathic symptoms are foot numbness and imbalance. On examination, there is sensory loss affecting mainly vibration and position sense but also some degree of temperature perception but no or minor muscular weakness and a diffuse areflexia. The course is rapid with development of an ataxic, broad-based gait in most patients at the time of examination [14•]. Misdiagnosis is often CIDP [28•]. This phenotype could result from massive endoneurial amyloid deposits in sensory nerves [14•], lumbar root ganglia, or nerve roots.
8 178 30 y
15
Israel
USA (Rochester)
Japan (Nagoya)
Patients with no Portuguese origin
NNERf French center for FAP
6y
6y
NS
20 y
2.9 y
NS
2y
3.3 y
4.3 y
6.1 y
93 %
+++
100 %
76 %
100 %
86 %
/ 77 %
41 %
53 %
43 %
63 % 58 % 46 %c
33 %
NS
100 %
21 %
12.5 % 25 %
29 %
27 %
20 %
/ 25 %
-
35
2
6
2
8
28 12
0%
NS
25 %
24 %
33 %
36 %
/ 60 % 48 %c
Late Very Met30 Other Positive onset late TTR TTR family (>50 y) onset Variant % variants history (>70 y) N=
100 %
NS
NS
76 %
NS
NS
/ 62 % (73 %c)
AFPNP 87 % SFPNP 13 %
NS
LD PNP
LD PNP ++ SFPNP 20 % LD PNP ++
/ SFPNP AFPNP Ataxic UL NPT Ataxic
S2: 13 % S3: 13 %
NS
NS
NS
(13 %)
47 %
NS
62 %
71 %
S3: 60 % 60 % at 4.6 y. NS 40 %
S3: 1
/ / S2: 35 % 80 %
Method of diagnosis sensitivity for amyloidosis
NB: 6/11 (55 %) AF: 37 %
NS
NS
NB: 80 % (93%a)
AF, EH, NB NS
NB: 3/5
53 % NB: 80 % AF: 1/5 (20 %)
NS
43 % NB: 11/12 (92 %)
/ / 42 % NB: 84.6 %a LSGB B : 64 %
Initial Phenotype Walking Autonomic OH misdisability dysfunction diagnosis Stage 2 % % (S2) Stage 3 (S3)
AF abdominal fat, AFPNPAll fiber polyneuropathy, Ataxic ataxic neuropathy EB endomyocardial biopsy, LD PNP length dependent polyneuropathy, LSGB labial salivary gland biopsy, NB nerve biopsy, NS not specified, OH orthostatic hypotension, SF PNP small fiber polyneuropathy, Stage 1 walking unaided, Stage 2 (S2) walking with cane, Stage 3 (S3) wheelchair bound, TTR-FAP transthyretin familial amyloid polyneuropathy, UL NPT neuropathy with upper limb onset
c
b
After serial nerve sections
17
Italy (Verona)
Cappellari et al, 2011 Leibou et al, 2012 ArrudaOlson et al, 2013 Koike et al, 2011
a
15
Luigetti et Italy (Rome) al, 2013
30 y 3y
15
Dohrn et Germany al, 2013 Belgium (Aachen)
/ 3.2 y
N = Period Mean delay from onset to diagnosis
386 23 y 60 3 y
Country (Center)
Adams et France (NNERf b) al, 2012
Article
Table 1 Presentation of TTR-FAP in varied countries and continents during the last 3 years
Curr Neurol Neurosci Rep (2014) 14:435 Page 3 of 12, 435
435, Page 4 of 12
Motor Phenotype TTR-FAP may also mimic amyotrophic lateral sclerosis (ALS) or motor polyradiculoneuropathy [29, 30]. As of now, 11 cases of TTR-FAP with predominantly motor involvement are reported [11, 13, 27•, 30]. These cases are due to 6 different TTR variants including Val93Met newly described [29]. They mimic ALS with bulbar and upper limb motor involvement, fasciculation, weakness and muscle atrophy [11, 13]. Clinical sensory manifestations are rare [11] but nerve conduction study (NCS) shows reduction of sensory nerve amplitudes; autonomic dysfunction is not predominant. Nerve biopsy reveals amyloid deposits [29, 30]. Upper Limb Onset Neuropathy Paresthesia or pain distinct from carpal tunnel syndrome are inaugural of upper limb onset neuropathy; on examination sensory and weakness predominate or exclusively affect upper limbs, usually asymmetrically. It has been reported in 2 Val30Met TTR-FAP patients [31] and in 22 % of French TTR-FAP patients of non-Portuguese origin [21•] with many TTR variants [32]. The mean delay for diagnosis is 4 years. These patients are usually later onset and male. Main initial misdiagnoses are CTS, idiopathic polyneuropathy, paraneoplastic neuropathy, CIDP, motor neuron diseases, and spinal cervical arthrosis.
Course of TTR-FAP Neuropathy of TTR-FAP is typically a slowly progressive polyneuropathy, walking difficulties requiring aid occur after a delay of 6 years (stage 2) and confinement to wheelchair (stage 3) at 10 years [2]. Late-onset Val30MetTTR-FAP is more severe and progresses twice as fast as early-onset presentation [33••]. The mean delay to reach stage 2 is only 2.6 years, and to reach stage 3, 3.8 years [33••]. In other variants of TTR, 60 % of patients reach stage 3 in a delay of 4.6 years [14•]. Life expectancy is reduced to 7.3 years [33••]. Unusually rapid decline in neurologic deficits has been reported in Ala97Ser TTR-FAP patients [20]. A recent study showed a significant positive correlation between levels of de novo anti ATTR antibodies at positions 24–35 of TTR and the age at FAP onset in Val30Met-FAP patients [34]. These findings may help explain the differences in early- and late-onset FAP.
Beta 2 Microglobulin-FAP A new amyloid variety of hereditary autosomal dominant systemic amyloidosis with neuropathy has been reported. It
Curr Neurol Neurosci Rep (2014) 14:435
is related to an Asp76Asn variant β2-microglobulin heterozygous for a single base substitution c.286G→A (GAT/AAT). Manifestations start in the sixth decade, associating progressive gastrointestinal symptoms, autonomic neuropathy and weight loss. The affected members of these kindred had normal circulating β2-microglobulin values [35••].
Genetic Counseling Genetic counseling is simple and clear in early onset Met30TTR-FAP (
NERVE AND MUSCLE (L WEIMER, SECTION EDITOR)
FAP Neuropathy and Emerging Treatments David Adams & Marie Théaudin & Cecile Cauquil & Vincent Algalarrondo & Michel Slama
# Springer Science+Business Media New York 2014
Abstract Transthyretin familial amyloid polyneuropathy (TTR-FAP) classically presents as a length dependent small fiber polyneuropathy in endemic countries like Portugal. In nonendemic countries, it may mimic a variety of chronic polyneuropathies, with several phenotypes: ataxic, upper limb onset neuropathy, or motor. In these cases, there is usually a late onset and no positive family history. TTR gene sequencing appears the most pertinent first-line test for diagnosis. Cardiac involvement of various severities is common in FAP. Liver transplantation remains the standard antiamyloid therapy with better results in Val30Met TTR-FAP of early onset. Antiamyloid medication has been developed. (1) TTR stabilizers: Tafamidis was the first drug approved in Europe in stage 1 (walking unaided) TTR-FAP to slow progression of the disease; diflunisal has been assessed in a phase 3 clinical trial; (2) TTR gene silencing is a new strategy to inhibit production of both mutant and nonmutant TTR with antisense oligonucleotides or SiRNA (2 ongoing phase 3 clinical trials). Keywords Familial amyloid polyneuropathy . Transthyretin . Nonmutant . Mutant . Mutations . Late onset . Sporadic . This article is part of the Topical Collection on Nerve and Muscle D. Adams : M. Théaudin : C. Cauquil : V. Algalarrondo : M. Slama APHP, HUPS, Univ Paris Sud, le Kremlin Bicêtre Cedex, France D. Adams (*) : M. Théaudin : C. Cauquil Department of Neurology, CHU Bicêtre, 78 rue du général leclerc, 94275 le Kremlin Bicêtre Cedex, France e-mail: [email protected] V. Algalarrondo Department of Cardiology (NNERf), CHU Antoine Beclere, Clamart, France D. Adams : M. Théaudin : V. Algalarrondo : M. Slama Inserm U788, French Referral Center for Familial Amyloid Polyneuropathy (NNERf), Paris, France
Diagnosis . Nerve biopsy . Labial salivary gland biopsy . TTR gene analysis . Liver transplantation . Tafamidis . RNAi therapy . Antisense oligonucleotide . Genetic counseling . Anticipation . Diagnosis . Heterogeneity . Pacemaker . Domino liver transplantation
Introduction Transthyretin familial amyloid polyneuropathy (TTR-FAP) is a rare systemic disease due to endoneurial amyloid deposit [1]. TTR-FAP is the most severe and disabling hereditary peripheral neuropathy occurring in adults. It is an autosomal transmission disease due to a point mutation of the TTR gene. The most common presentation is that of a length dependent peripheral and autonomic neuropathy with predominantly small fiber involvement associated with cardiomyopathy and significant weight loss. The disease is progressive, irreversible, disabling, leading to progressive disability. It is also lifethreatening; patients may die from cachexia, severe infection, or sudden death within 12 years from onset [2]. Overall prevalence of TTR-FAP is estimated to be 0.87–1.1 per 1, 000, 000 persons [3]. TTR-FAP has long been considered an endemic disease in north Portugal [4], Japan [3], and Sweden [5] reaching 9×10-6 (1:909 inhabitants) to 11–15.5× 10-6 (1:1108 inhabitants) in Nagano prefecture [3], Skelleftea in Sweden [5], and district of Povoa or Vila do Conde in Portugal [4]. Early onset is usual in Portugal and Japan (87 % of patients developing symptoms before 40 years of age) [4] whereas a late onset (87 % developing symptoms after 40 years of age) is classic in Sweden [5]. In the last 20 years, sporadic cases have been reported in Europe initially in France and UK, with a variety of TTR gene mutations including Val30Met [6]. Among Val30Met TTRFAP, late onset cases differ from early-onset cases by impairment of both superficial and deep sensory fibers with rare and
435, Page 2 of 12
mild autonomic symptoms, male predominance, and inconstant positive family history (50 %) [7, 8]. Concerning therapy, liver transplantation (LT), initially proposed 20 years ago as a treatment of TTR–FAP, suppresses the main source of variant TTR [9] and may stop disease progression. As of now, more than 2000 patients underwent LT in the world [10•]. Major and constant progress has been achieved in TTR-FAP in the last decades. In this review, we will focus on new and interesting findings in the spectrum of the disease, in therapy and therapeutic perspectives.
FAP Neuropathies Are Ubiquitous TTR-FAP is becoming clearly a world-wide disease often appearing to be a sporadic disease. TTR-FAP patients has been diagnosed in many continents; more recently in European countries such as Italy [11, 12•, 13], and Germany [14•], in North America including USA [15•] and central America [16, 17], and in Asia [18–20]. The incidence of TTR-FAP in national reference centers for FAP or amyloidosis is low but varies from 1 new case every 2 years [14•] to 20 new cases/ year [21•] (Table 1).
Curr Neurol Neurosci Rep (2014) 14:435
Biopsy for Diagnosis of TTR-FAP Biopsy is required in diagnosis of amyloidosis, in order to identify typical amyloid deposits by Congo red staining that demonstrates apple-green birefringence under cross-polarized light. However, sensitivity of biopsies is incomplete and the absence of amyloid deposit finding does not exclude the diagnosis; multiple biopsies can be necessary in some patients to reach the diagnosis. The sensitivity is low in abdominal fat ranging from 20 %–37 % [11, 12•], higher in labial salivary gland biopsy (LSGB) varying from 64 % [21•] to 91 % [23], and nerve biopsy ranging from 55 % [12•, 18] to 80 %–92 % [11, 14•, 21•]. Sensitivity varies widely from 1 center to another depending on experience and technique. TTR Gene Analysis Among the 100 TTR gene mutations, a majority are amyloidogenic, but some are only polymorphisms [24]. TTR gene analysis is largely used as a diagnostic tool in endemic countries looking for Val30Met variant, more rarely in nonendemic countries, where TTR gene sequencing allows identification of new mutations [14•, 25, 26, 27•] among patients with pathologically proven amyloid neuropathy.
Genetic Heterogeneity in TTR-FAP Val30Met is the most frequent genotype in the world and is by far the main mutation in Portugal and Sweden; however, the incidence differs considerably between countries. This mutation is not described in Mexico [16] or Taiwan [20] and approaches 50 % of cases in France [21•]. There is increasing genetic heterogeneity in many countries including 19 variants in Japan [22], 20 in Italy [13], 29 in France [21•], and 34 in the USA [15•] (Table 1).
Diagnosis of TTR-FAP Diagnosis of TTR-FAP remains difficult and requires expertise and adequate diagnostic methods. The delay between the first clinical signs and diagnosis varies from 2–6 years (Table 1). Main reasons are: absence of family history, atypical clinical presentations (varied phenotypes), inconstant autonomic dysfunction, difficulties to detect amyloid deposits in a single tissue biopsy, and rare use of TTR gene analysis in the screening of idiopathic polyneuropathy. Tools for Diagnosis Adequate diagnostic tools include biopsy to detect amyloid deposits and TTR gene sequencing to identify an amyloidogenic TTR gene mutation.
Spectrum of Phenotypes in TTR-FAP In endemic areas, TTR-FAP has a stereotypical presentation as a length dependent small fiber polyneuropathy mimicking diabetic polyneuropathy or as an inaugural autonomic neuropathy with digestive disorders or impotence, in association with weight loss [2]. In late onset Val30Met TTR-FAP (>50 years), both superficial and deep sensation are impaired with inconstant mild autonomic symptoms [8]. Many new clinical phenotypes have been recently identified, usually initially misleading diagnosis. Ataxic Phenotype An ataxic phenotype was recently reported in France in up to 26 % of TTR-FAP [21•] and in Germany [14•], usually with a non Met30TTR variant [14•, 21•]. Initial neuropathic symptoms are foot numbness and imbalance. On examination, there is sensory loss affecting mainly vibration and position sense but also some degree of temperature perception but no or minor muscular weakness and a diffuse areflexia. The course is rapid with development of an ataxic, broad-based gait in most patients at the time of examination [14•]. Misdiagnosis is often CIDP [28•]. This phenotype could result from massive endoneurial amyloid deposits in sensory nerves [14•], lumbar root ganglia, or nerve roots.
8 178 30 y
15
Israel
USA (Rochester)
Japan (Nagoya)
Patients with no Portuguese origin
NNERf French center for FAP
6y
6y
NS
20 y
2.9 y
NS
2y
3.3 y
4.3 y
6.1 y
93 %
+++
100 %
76 %
100 %
86 %
/ 77 %
41 %
53 %
43 %
63 % 58 % 46 %c
33 %
NS
100 %
21 %
12.5 % 25 %
29 %
27 %
20 %
/ 25 %
-
35
2
6
2
8
28 12
0%
NS
25 %
24 %
33 %
36 %
/ 60 % 48 %c
Late Very Met30 Other Positive onset late TTR TTR family (>50 y) onset Variant % variants history (>70 y) N=
100 %
NS
NS
76 %
NS
NS
/ 62 % (73 %c)
AFPNP 87 % SFPNP 13 %
NS
LD PNP
LD PNP ++ SFPNP 20 % LD PNP ++
/ SFPNP AFPNP Ataxic UL NPT Ataxic
S2: 13 % S3: 13 %
NS
NS
NS
(13 %)
47 %
NS
62 %
71 %
S3: 60 % 60 % at 4.6 y. NS 40 %
S3: 1
/ / S2: 35 % 80 %
Method of diagnosis sensitivity for amyloidosis
NB: 6/11 (55 %) AF: 37 %
NS
NS
NB: 80 % (93%a)
AF, EH, NB NS
NB: 3/5
53 % NB: 80 % AF: 1/5 (20 %)
NS
43 % NB: 11/12 (92 %)
/ / 42 % NB: 84.6 %a LSGB B : 64 %
Initial Phenotype Walking Autonomic OH misdisability dysfunction diagnosis Stage 2 % % (S2) Stage 3 (S3)
AF abdominal fat, AFPNPAll fiber polyneuropathy, Ataxic ataxic neuropathy EB endomyocardial biopsy, LD PNP length dependent polyneuropathy, LSGB labial salivary gland biopsy, NB nerve biopsy, NS not specified, OH orthostatic hypotension, SF PNP small fiber polyneuropathy, Stage 1 walking unaided, Stage 2 (S2) walking with cane, Stage 3 (S3) wheelchair bound, TTR-FAP transthyretin familial amyloid polyneuropathy, UL NPT neuropathy with upper limb onset
c
b
After serial nerve sections
17
Italy (Verona)
Cappellari et al, 2011 Leibou et al, 2012 ArrudaOlson et al, 2013 Koike et al, 2011
a
15
Luigetti et Italy (Rome) al, 2013
30 y 3y
15
Dohrn et Germany al, 2013 Belgium (Aachen)
/ 3.2 y
N = Period Mean delay from onset to diagnosis
386 23 y 60 3 y
Country (Center)
Adams et France (NNERf b) al, 2012
Article
Table 1 Presentation of TTR-FAP in varied countries and continents during the last 3 years
Curr Neurol Neurosci Rep (2014) 14:435 Page 3 of 12, 435
435, Page 4 of 12
Motor Phenotype TTR-FAP may also mimic amyotrophic lateral sclerosis (ALS) or motor polyradiculoneuropathy [29, 30]. As of now, 11 cases of TTR-FAP with predominantly motor involvement are reported [11, 13, 27•, 30]. These cases are due to 6 different TTR variants including Val93Met newly described [29]. They mimic ALS with bulbar and upper limb motor involvement, fasciculation, weakness and muscle atrophy [11, 13]. Clinical sensory manifestations are rare [11] but nerve conduction study (NCS) shows reduction of sensory nerve amplitudes; autonomic dysfunction is not predominant. Nerve biopsy reveals amyloid deposits [29, 30]. Upper Limb Onset Neuropathy Paresthesia or pain distinct from carpal tunnel syndrome are inaugural of upper limb onset neuropathy; on examination sensory and weakness predominate or exclusively affect upper limbs, usually asymmetrically. It has been reported in 2 Val30Met TTR-FAP patients [31] and in 22 % of French TTR-FAP patients of non-Portuguese origin [21•] with many TTR variants [32]. The mean delay for diagnosis is 4 years. These patients are usually later onset and male. Main initial misdiagnoses are CTS, idiopathic polyneuropathy, paraneoplastic neuropathy, CIDP, motor neuron diseases, and spinal cervical arthrosis.
Course of TTR-FAP Neuropathy of TTR-FAP is typically a slowly progressive polyneuropathy, walking difficulties requiring aid occur after a delay of 6 years (stage 2) and confinement to wheelchair (stage 3) at 10 years [2]. Late-onset Val30MetTTR-FAP is more severe and progresses twice as fast as early-onset presentation [33••]. The mean delay to reach stage 2 is only 2.6 years, and to reach stage 3, 3.8 years [33••]. In other variants of TTR, 60 % of patients reach stage 3 in a delay of 4.6 years [14•]. Life expectancy is reduced to 7.3 years [33••]. Unusually rapid decline in neurologic deficits has been reported in Ala97Ser TTR-FAP patients [20]. A recent study showed a significant positive correlation between levels of de novo anti ATTR antibodies at positions 24–35 of TTR and the age at FAP onset in Val30Met-FAP patients [34]. These findings may help explain the differences in early- and late-onset FAP.
Beta 2 Microglobulin-FAP A new amyloid variety of hereditary autosomal dominant systemic amyloidosis with neuropathy has been reported. It
Curr Neurol Neurosci Rep (2014) 14:435
is related to an Asp76Asn variant β2-microglobulin heterozygous for a single base substitution c.286G→A (GAT/AAT). Manifestations start in the sixth decade, associating progressive gastrointestinal symptoms, autonomic neuropathy and weight loss. The affected members of these kindred had normal circulating β2-microglobulin values [35••].
Genetic Counseling Genetic counseling is simple and clear in early onset Met30TTR-FAP (
