Brain, Vol. 123, No. 7, 1495-1504,
July 2000
© 2000 Oxford University Press
The course and prognostic factors of familial amyloid polyneuropathy after liver transplantation
1 Service de Neurologie and Laboratoire Louis Ranvier, 2 Service d'explorations fonctionnelles du système nerveux and 3 Département d'Epidémiologie, INSERM U 292, Hôpital de Bicêtre, Le Kremlin-Bicêtre, 4 Centre Hépato-Biliaire, Hôpital Paul-Brousse, Villejuif, Assistance Publique Hôpitaux de Paris, Université de Paris Sud, France, 5 Third Department of Internal Medicine, Miyazaki Medical College, Miyazaki, Japan and 6 Centro de Estudos de Paramyloidosis, Santo Antonio, Porto, Portugal
Correspondence to:
Dr David Adams, Service de Neurologie, Hôpital de Bicêtre, Le Kremlin-Bicêtre, 94275 Cedex, France
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Abstract |
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Familial amyloid polyneuropathy (FAP) associated with mutations of the transthyretin (TTR) gene is the most common type of FAP, a devastating disease causing death within 10 years after the first symptoms. Because most of the amyloidogenic mutated TTR is secreted by the liver, transplantation is widely used to treat these patients, but long-term quantitative evaluation of the effects of liver transplantation on the progression of the neuropathy are not available. We have treated 45 patients with symptomatic TTR-FAP, including 43 with the Met30 TTR gene mutation, and report on the results of periodic evaluation of markers of neuropathy in 25 of them, who have been followed for more than 2 years after liver transplantation (mean follow-up 4 years). The overall survival rates at 1 and 5 years were 82 and 60%, respectively. Urinary incontinence and a low Norris score at liver transplantation were associated with poorer outcome. The motor score stabilized in seven of 11 patients (64%) with mild sensorimotor neuropathy (walking unaided) and in two of the eight patients (25%) with severe sensorimotor deficit (walking with aid) at liver transplantation. In five other patients, deterioration of motor deficit occurred only within the first year after liver transplantation, but was progressive after this interval in two patients. None of the six patients with pure sensory neuropathy developed motor loss and superficial sensory loss remained unchanged. Two years after liver transplantation, the rate of myelinated axon loss in nerve biopsy specimens was markedly lower in seven transplanted patients (0.9/mm2 of endoneurial area/month) than in non-transplanted patients (70/mm2 of endoneurial area/month). Symptoms of dysautonomia and quantitated cardiocirculatory autonomic tests remained unchanged. In all patients, serum mutated TTR decreased to 2.5% of pre-liver transplantation values and remained at this level during follow-up. We presently recommend liver transplantation in FAP patients at onset of first symptoms and exclusion of those with a Norris score below 55 and/or with urinary incontinence.
familial amyloid polyneuropathy; liver transplantation; transthyretin mutation; course
CMAP = compound muscle action potential; FAP = familial amyloid polyneuropathy; SNAP = sensory nerve action potential; TTR = transthyretin
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Introduction |
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Familial amyloidotic polyneuropathies (FAPs) are autosomal dominant polyneuropathies due to polyvisceral amyloid deposits that predominate in the endoneurial space of peripheral nerves. Since its original description in Portugal, where more than 500 families are affected, FAP has been reported in many countries. The first symptoms usually occur during the third decade of life (Andrade, 1952
; Coutinho et al., 1980). The patients subsequently develop a progressive sensorimotor neuropathy with autonomic dysfunction, weight loss, and frequent cardiac and renal involvement leading to death within a mean of 10.8 years (Coutinho et al., 1980). More than 50 point mutations of the TTR gene have been identified, the most common being the Val
Met30, which causes the disease in Portugal (Saraiva, 1995), Sweden (Andersson, 1976) and Japan (Araki et al., 1980). In France, 10 point mutations of the TTR gene have been identified so far, all leading to development of the same pattern of neuropathy (Planté-Bordeneuve et al., 1998). Recently, liver transplantation has been proposed as a means of treating this condition as the liver is the main source of TTR, as shown by in situ hybridization (Jacobsson, 1989), Northern blot analysis (Soprano et al., 1985) and by the dramatic reduction of abnormal serum TTR levels in the first patients who have been operated on (Holmgren et al., 1991). The favourable clinical results in the first four patients (Holmgren et al., 1993) prompted several centres to perform liver transplantation in FAP patients (Steen et al., 1994), but long-term quantitative evaluation of neuropathic manifestations are not available. In addition, neuropathy and cardiomyopathy may be variably influenced by liver transplantation (Bergethon et al., 1996; Dubrey et al., 1997). We performed a prospective study in 25 patients with FAP followed for more than 2 years after liver transplantation, selected from a cohort of 45 patients operated on over the past 6 years. Quantitative analysis of clinical, electrophysiological and in some cases morphological markers was carried out. We also report on the evaluation of the post-liver transplantation complications and prognostic factors influencing the outcome of liver transplantation in this setting.
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Methods |
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Selection of patients, liver transplantation and regimen
The data of 45 patients (25 males, 20 females; mean age 41 years, range 25–68 years) were reviewed. The main clinical characteristics at inclusion are summarized in Table 1
. All patients had (i) clinical manifestations of polyneuropathy with autonomic disturbances; (ii) TTR-related amyloidosis with positive immunolabelling by anti-TTR antibodies of endoneurial congophilic deposits in nerve biopsy specimens, high serum variant TTR level on an ELISA (enzyme-linked immunosorbent assay) test and TTR gene mutation identified by DNA analysis in blood leucocytes; and (iii) all patients were ambulatory without general contraindication to liver transplantation (Consensus statement, 1994). They were selected from a total cohort of 59 symptomatic FAP patients. They underwent orthotopic cadaveric liver transplantation and received an ABO compatible graft, and received as immunosuppressive therapy a triple drug combination of cyclosporin A (Novartis, Basel, Switzerland), steroids and azathioprine (Gugenheim et al., 1987), or rabbit antithymocyte globulin (Merieux, France) in place of cyclosporin, during the first 10–14 days in order to protect the renal function, or a combination of tacrolimus (FK506, Fujisawa, Japan) and steroids.
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Methods of evaluation
Clinical, electrophysiological and morphological evaluations of neuropathic manifestations were performed.
Clinical evaluation
A functional score for limbs was established from a modified Norris scale (Lacomblez et al., 1989). Symptoms for autonomic dysfunction were evaluated by a questionnaire and graded accordingly. Muscle testing was performed in all four limbs. The clinical motor scores were obtained after assessment of 62 muscle functions according to the five-grade scale of the Medical Research Council. Evaluation of light touch, pinprick, vibratory and temperature sensations at 4°C and at 40°C, and position sense were tested to explore the functions of different subpopulations of axons. Cardiovascular autonomic function was assessed by measurements of the variation in blood pressure and pulse rate in the recumbent and standing positions, and the variation in heart-rate responses to postural change, to the Valsalva manoeuvre and to deep breathing was assessed. The study was approved by the ethical committee of the Hôpital de Bicêtre.
Electrophysiological testing
The amplitudes of sensory nerve action potentials (SNAPs), compound muscle action potentials (CMAPs) and nerve conduction velocities were measured in all four limbs. Results were obtained in the same laboratory with the same equipment (counterpoint; Dantec, Skorlunde, Denmark). Motor conduction velocity was measured in the median, ulnar, peroneal and popliteal nerves. SNAPs were evaluated in the sural, ulnar and median nerves. Motor and sensory electrophysiological scores were obtained by the sum of the amplitudes of CMAPs (
CMAPs) and of SNAPs (SNAPs), respectively, from both sides. Normal value for SNAPs was above 60 µV and for CMAPs was above 20 mV in an age-matched population.
Morphometric procedures
A nerve biopsy was performed before liver transplantation in patients 2–16 and was repeated on the opposite side 2 years later on the same nerve. All nerve specimens were fixed in buffered 3.6% isotonic glutaraldehyde at pH 7.4, then divided into three parts. One fragment was embedded in paraffin, cut at 6-µm thickness and examined after haematoxylin and eosin staining. The second fragment was embedded in epon. Thionin-stained 1-µm thick transverse sections were used for morphometry and 0.1-µm thick sections stained with uranyl acetate and lead citrate for electron microscopic examination. The third fragment was post-fixed in osmium tetroxide, then macerated in 66% glycerin for 48 h before dissection in pure glycerin. The density of myelinated fibres per mm2 was determined on the whole intrafascicular area. Four patients with FAP, for whom two consecutive nerve biopsies on homonymic nerves (same nerve on the other side of the body) had been necessary for diagnostic purposes before the availability of diagnosis by molecular genetics, were used as controls. Patients gave informed consent for biopsy.
Variant TTR assays
The serum level of the variant TTR was determined in an ELISA using a monoclonal antibody (FD6) (Costa et al., 1993) and by radioimmunoassay (Nakazato et al., 1984). Level of the variant TTR in the CSF was determined by radioimmunoassay in three patients.
Periodicity of evaluation
Clinical, electrophysiological and biological evaluations were performed less than 3 months before the liver transplantation and repeated every 6 months after surgery. Nerve biopsy was repeated 2 years after liver transplantation on the opposite side. The serum analysis was carried out 5 days after liver transplantation. Clinical evaluation was performed by the same physician (D.A.) and muscle testing by the same physiotherapists to avoid inter-operator variability.
Statistical analysis
The Kaplan–Meier analysis of survival was used. The comparison of the survival curves for the patients with and without characteristics was performed with the use of the log-rank test. The Cox regression model was used to determine the significant independent prognostic factors (Cox, 1972). Differences between group means were analysed by the Wilcoxon Rank Sum Test. The comparison of the percentages was performed using 
2 test.
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Results |
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Patients' characteristics
From March 1993 to March 1999, 45 patients fulfilling the three criteria described in the Methods section underwent liver transplantation; two also had a kidney transplantation for severe amyloid nephropathy. The patients were selected from a population of 59 symptomatic FAP patients and the clinical characteristics of treated FAP patients are summarized in Table 1
. At inclusion, the mean duration of symptoms of neuropathy was 4.3 years and all except two had the Met30 TTR gene mutation. Thirty patients were able to walk without help including 18 with mild sensorimotor and 12 with pure sensory deficit. The other 15 patients had severe sensorimotor neuropathy and needed aid for walking. All patients had symptomatic autonomic dysfunction. Four patients had a cardiac pacemaker. Fourteen patients were excluded because of a disabling sensorimotor neuropathy. Twelve were wheelchair bound or bedridden and the other two were 70-year-old patients walking with aid. Ten patients were of French origin and 10 had a Met30 TTR gene mutation. The mean age was 57 years and the mean duration of the disease was 7 years.
Variant TTR in the serum and CSF
In all patients the variant TTR levels measured with ELISA returned to normal values within days after liver transplantation. Radioimmunoassay showed a 95–98% reduction of serum variant Met30 TTR levels which persisted 5 years after liver transplantation. The mean concentration of Met30 TTR in the serum was 9.05 ± 2.60 mg/dl before liver transplantation versus 0.23 ± 0.13 mg/dl after liver transplantation. Levels of variant TTR in the CSF decreased to 50% of pre-liver transplantation values in two patients and remained unchanged in one (data not shown).
Evaluation of the neurological deficit
The results of the 25 patients who had been followed more than 24 months after liver transplantation were analysed. Nine had died during this interval, the follow-up was shorter in nine and two were lost to follow-up. We analysed separately patients with pure sensory neuropathy (n = 6), those with mild sensorimotor neuropathy who could walk unaided at liver transplantation (n = 11) and those with severe sensorimotor neuropathy who needed aid for walking at liver transplantation (n = 8). The mean follow-up was 48 months (range 24–75 months).
Clinical and electrophysiological assessments
Clinical and electrophysiological motor scores remained unchanged in 13 of 17 patients (76%) who walked unaided at liver transplantation and in 15 of 22 patients (68%) with a Norris score >55 at liver transplantation, but progressed in six of eight patients (75%) who walked with aid at liver transplantation and in all three patients with a Norris score 
55.
In the 11 patients with mild sensorimotor neuropathy, clinical and electrophysiological motor scores remained unchanged in seven patients (64%), including four followed for 5 years or more (Fig. 1). The clinical motor score decreased in four patients (36%), which occurred in all four limbs in two, and two patients needed aid for walking after liver transplantation. The electrophysiological motor score also decreased in two of three patients with recordable CMAPs at liver transplantation. Deterioration occurred only within the first year after liver transplantation in two patients, but was progressive after this interval in patient 18.
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In the subgroup of eight patients with a severe neurological deficit, the clinical motor score decreased in six patients (75%), which occurred in all four limbs in five (Fig. 2A and B
) and there was worsening of walking ability in four (50%) (Fig. 2C). Two patients became bedridden and eventually died from severe infection 2 years after liver transplantation. Among the four patients followed for more than 4 years, deterioration occurred in the first year after liver transplantation, but the motor score remained unchanged after that time in three. The condition of patient 5 deteriorated steadily and he became bedridden and eventually died from cardiac insufficiency 47 months after liver transplantation. Among the three patients with recordable CMAPs at liver transplantation, electrophysiological motor scores remained stable in all. None of the six patients with pure sensory neuropathy developed motor deficit during follow-up.
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Distribution of superficial sensory loss remained unchanged in 20 of 25 patients. Gradual reduction of the pain and in the area of temperature sensory loss was noted in the limbs and over the trunk in two patients with mild sensorimotor deficit and two with pure sensory neuropathy. Conversely, in patient 5, superficial and vibratory sensory loss extended gradually with deterioration of his motor score. Among the 12 patients with recordable SNAPs at liver transplantation, the electrophysiological sensory score remained unchanged in five patients, including four with pure sensory neuropathy, and was decreased in seven.
Morphological study
Among the 15 patients who underwent a nerve biopsy before liver transplantation, nine had a second nerve biopsy 2 years after liver transplantation. Five patients died before this interval and one refused the biopsy. The nerve biopsied in operated patients was the sural nerve in five, the superficial peroneal nerve in two, and the superficial branch of the radial nerve in two and in control patients, the sural nerve or the peroneal nerve. The mean interval between the two biopsies was 25 months in operated patients and 14 months in control patients. The mean density of myelinated fibres per mm2 of endoneurial area in nerve biopsies was 1082 before liver transplantation versus 1108 per mm2 2 years after liver transplantation. The mean density of fibres lost per month was 0.9 fibres/mm2 in transplanted patients versus 70 in four control patients with FAP (P < 0.001) (Table 2).
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Autonomic dysfunction
Most symptoms of autonomic dysfunction remained unchanged after liver transplantation. However, three of five patients with severe daily diarrhoea partially improved; two had alternating diarrhoea and constipation, and one appeared to have a better social life, but he still had daily diarrhoea and took loperamide. Frequency of crisis of vomiting decreased in one out of five affected patients. Nine out of twelve patients still complained of dysuria and one still needed intermittent urethral catheterization 6 years after liver transplantation. Urinary incontinence was unchanged in five patients with stable urodynamic studies. All males remained impotent. Moreover, symptoms worsened in five patients; one developed an untractable crisis of vomiting, which needed artificial nutrition, two manifested alternating diarrhoea and constipation, and one developed urinary incontinence. Postural hypotension remained unchanged in eight patients and appeared in two after liver transplantation. All cardiocirculatory tests remained abnormal except in three patients who still had normal variation of R–R interval during the Valsalva manoeuvre and deep breathing.
General manifestations after liver transplantation
Mortality
The estimated survival rate for the liver transplantation group at 1 and 5 years is 82 and 60%, respectively. Fourteen out of the 45 patients of the cohort died after liver transplantation, including eight within 6 months after surgery. The causes of death were severe systemic infection and/or multiorgan failure (seven), or cardiac arrest (one). Six patients died between 17 and 46 months after liver transplantation, including three from severe infection, one from cardiac failure, one suddenly and one who committed suicide. Three of the four patients with a cardiac pace-maker at liver transplantation died.
Factors significantly associated with a higher post-transplantation mortality include: severe sensorimotor neuropathy with a Norris score below 55/81; permanent urinary incontinence; postural hypotension with a fixed pulse rate; and to a lesser extent a pre-liver transplantation weight loss >20% (Table 3 and Fig. 3). The duration of the disease, the age of the patient or symptoms of severe diarrhoea were not risk factors for post-liver transplantation mortality. Multivariate analysis showed that urinary incontinence [P = 0.001; the relative risk, RR = 6.7, 95% CI (confidence interval) = 2.1–21.4] and a low Norris score (P = 0.01; RR = 4.3, 95% CI = 1.4–13.3) were independent risk factors.
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The estimated survival rate in the untreated group at 5 years was 23% and was similar to the liver transplantation group with comparable severity (Norris score
55) (Fig. 4); 11 patients died.
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Morbidity
Thirty-three patients (73%) developed infections, which were multiple in 22 of them (49%), mainly during the first year after liver transplantation. Fourteen patients (31%) developed one or several episodes of septicaemia, which led to death in seven. In five patients the infection had a urinary origin. The risk of developing multiple septicaemia, which occurred in six patients, was 55% in patients with urinary incontinence versus 3% in patients without incontinence (P < 0.001) and 40% in patients with severe sensorimotor neuropathy versus 0% in the others (P < 0.001). Eighteen patients (40%) developed urinary tract infection, which was recurrent in nine. Nine patients developed a pulmonary infection, which was opportunistic in six. Patient 27 developed gangrene of the right foot, which required leg amputation 30 months after liver transplantation.
Acute liver rejection occurred in 18 patients, which was resolved in 11 patients after pulses of methyl prednisolone and in one after a higher dose of cyclosporin; six patients were switched from cyclosporin to tacrolimus due to corticosteroid resistant rejection. Two patients underwent a second liver transplantation because of a severe herpetic hepatitis and primary non-function of the graft. Two patients developed a lymphoma in the liver graft, 2 and 5 months after liver transplantation, which resolved after chemotherapy in one. The other patient also developed an acute graft versus host disease. Both patients died from septic complications. Five patients (11%) became depressed after liver transplantation; three patients attempted suicide, which was lethal in one.
Weight variation and other organ manifestations
After liver transplantation, 12 patients (48%) gained weight (mean 6.7 kg, range 2–17 kg), three returning to their premorbid weight, seven (28%) lost weight (mean 9.7 kg, range 3–23) and the weight remained unchanged in six patients (24%). Patients 5, 7 and 9 required implantation of a cardiac pacemaker 1.5, 2 and 5 years, respectively, after liver transplantation, for complete atrioventricular heart block. Two patients were operated on for glaucoma or vitreous opacities after liver transplantation.
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Discussion |
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Liver transplantation, which suppresses the main source of the amyloidogenic mutated TTR, is widely recommended for treatment of FAP. Our results confirm that a rapid and steady decrease of circulating mutated TTR in the serum follows liver transplantation (Holmgren et al., 1991
), but the variable effects on the neurological deficit and the high post-transplantation mortality rate require further analysis to determine the usefulness of liver transplantation in FAP. The results of liver transplantation and the major decrease of serum variant TTR levels on different markers of neuropathy were variable.
The neurological deficit did not progress in most patients with mild neuropathy at liver transplantation, according to clinical parameters assessed during the mean 4-year follow-up period, in 76% of those who walked unaided at liver transplantation and in 68% with a Norris score >55. This course differs markedly from the natural history of the disease, which is progressive and unremitting (Coutinho et al., 1980). However, we have not seen any improvement in motor function or in walking ability, even in patients with moderate weakness before transplantation. This contradicts previous reports (Parrilla et al., 1997) of dramatic improvement within 2 years after liver transplantation and recovery in affected muscles from complete paralysis to movement against resistance (Bergethon et al., 1996). Reduction of the area of sensory loss was observed in four patients with mild sensory motor neuropathy or pure sensory neuropathy, as previously reported (Bergethon et al., 1996).
Morphological studies of sensory nerve biopsy specimens showed a dramatic reduction of nerve fibre loss in transplanted patients compared with controls with FAP. Evaluation of the density of myelinated fibres in nerve specimens at two time points was performed to see whether liver transplantation reduced the rate of disappearance of nerve fibres seen in untreated patients. Quantitative evaluation of amyloid deposits in nerve samples was not carried out as it is unreliable due to the patchy and random distribution of amyloid deposits (Said et al., 1984; Sobue et al., 1990). These morphological data strengthen the clinical and electrophysiological assessments.
In spite of liver transplantation, the sensorimotor deficit progressed in 40% of the patients and predominated in those with dependent walking at the pre-transplantation evaluation or with a Norris score below 55, and was marked by worsening of walking ability in some patients. Deterioration usually occurred only in the first year following liver transplantation, but was progressive over this period in two patients with sensory motor neuropathy. This progressive deterioration, which involved two patients with a Met30 TTR gene mutation, has also been reported in a patient with a Tyr77 TTR gene mutation (Garcia-Herola et al., 1999).
The clinical effects of liver transplantation on autonomic dysfunction are rather disappointing. No improvement was found on quantitative evaluation of postural variation of arterial blood pressure, nor in non-invasive cardiovascular autonomic tests. Moreover, postural hypotension developed in some patients. Diarrhoea and impotence remained unchanged (Suhr et al., 1995). In contrast to previous reports (Suhr et al., 1995), sphincter disturbances remained unchanged with no improvement in quantitatively evaluated urodynamic tests.
Liver transplantation carries a high mortality rate in FAP patients, as reported in other papers in the literature (Suhr et al., 1995; Bergethon et al., 1996; Parrilla et al., 1997). The high incidence of post-operative infection in this population, facilitated by a poor general condition, neurogenic bladder dysfunction and immunosuppressive therapy, was a major cause of death (Bismuth et al., 1995), especially during the first 6 months after liver transplantation. The estimated survival rate at 5 years is 60%, as found by others (Parrilla et al., 1997), and is slightly lower than in our series of patients with chronic liver disease (Bismuth et al., 1995). In our patients the severity of the sensory motor neuropathy and autonomic neuropathy with presence of urinary incontinence were the major risk factors for post-liver transplantation mortality. There is no advantage in proceeding to liver transplantation in patients with severe sensorimotor neuropathy as survival rate at 5 years after liver transplantation is similar to a control group. We did not confirm that a longer duration of symptomatic disease or higher age carried a greater risk for death (Suhr et al., 1995). Identification of these risk factors could help for selection of patients with FAP for liver transplantation, especially in an endemic area like Portugal where liver grafts are insufficient for all FAP patients. Liver transplantation should not be recommended for patients with severe neuropathy and/or urinary incontinence. The presence of severe cardiac conduction disturbances at liver transplantation is probably a poor prognostic factor.
One patient was operated on 1 year after liver transplantation for amyloid vitreous deposits. Retinal epithelium seems to be a source of variant TTR (Cavallaro et al., 1990) and FAP patients remain at risk for ocular amyloidosis after liver transplantation (Ando et al., 1996). Development of severe atrioventricular conduction block in three patients and death from severe cardiac insufficiency in one, more than 1 year after liver transplantation, suggest secondary alteration of cardiac function, as recently reported (Dubrey et al., 1997).
We conclude that liver transplantation significantly reduces circulating mutated TTR and the rate of axonal degeneration, and may stop progression of the neurological deficit in patients with a mild deficit. The high post-operative mortality in severely affected patients justifies careful selection of patients for liver transplantation and exclusion of patients with urinary incontinence and/or severe sensorimotor neuropathy. The presence of cardiac involvement before liver transplantation seems to be associated with a poorer outcome. After liver transplantation, progression of the neuropathy may be related to variant TTR released in the CSF by choroid plexi migrating to the endoneurial space, or to an accumulation of the wild type of TTR in pre-transplantation amyloid deposits.
Acknowledgements
We wish to thank Dr J.-M. Léger, Dr M. Haguenau, Dr P. Bouche, Dr F. Mikol, Dr P. Chaine, Dr F. Dubas, Dr L. Chia, Dr J. C. Antoine, Dr F. Thedrez, Dr H. Abdelmoumni, Dr M. Delahousse, Dr J. Emmerich, Dr P. Brunet, Dr T. Coelho and Dr C. Lamy, and Josette Bacci, Olivier Trassard, Chantal Declerck, Catherine Bourges and Wendy Phillips for collaboration. This work was supported by grants from the `Association pour la lutte contre l'Amylose Paulette Ghiron-Bistagne', the University of Paris-Sud, the Assistance Publique des Hopitaux de Paris, and the Association Franciaise de lutte contre la Myopathie.
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Received November 1, 1999. Revised December 20, 1999. Accepted January 31, 2000.
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G. Blevins, R. Macaulay, S. Harder, D. Fladeland, T. Yamashita, M. Yazaki, K. Hamidi Asl, M. D. Benson, and J. R. Donat Oculoleptomeningeal amyloidosis in a large kindred with a new transthyretin variant Tyr69His Neurology, May 27, 2003; 60(10): 1625 - 1630. [Abstract] [Full Text] [PDF]
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M Buttmann, M Marziniak, K V Toyka, C Sommer, and K Altland "Sporadic" familial amyloidotic polyneuropathy in a German patient with B cell lymphocytic leukaemia J. Neurol. Neurosurg. Psychiatry, July 1, 2002; 73(1): 86 - 87. [Full Text] [PDF]
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S.-i. Ikeda, M. Nakazato, Y. Ando, and G. Sobue Familial transthyretin-type amyloid polyneuropathy in Japan: Clinical and genetic heterogeneity Neurology, April 9, 2002; 58(7): 1001 - 1007. [Abstract] [Full Text] [PDF]
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E. Hund, R. P. Linke, F. Willig, and A. Grau Transthyretin-associated neuropathic amyloidosis: Pathogenesis and treatment Neurology, February 27, 2001; 56(4): 431 - 435. [Abstract] [Full Text] [PDF]
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