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Background: Transthyretin amyloidosis due to V30M mutation (ATTR-V30M) is the most frequent hereditary ATTR amyloidosis. Besides neurophysiological measures, there are no biomarkers to detect precl...

There have now been randomized controlled trials of four different therapeutics for hereditary amyloid polyneuropathy related to transthyretin (TTR) deposition and one for amyloidotic cardiomyopathy of both genetic and sporadic origin. It is likely that in the next few months those not already approved by either the US Food and Drug Administration (FDA) and/or the European Medicines Authority (EMA) will receive similar approvals for treatment for all or particular groups of patients. This is a far cry from circumstances less than 10 years ago when the only available therapy was gene replacement by liver transplant. The randomized controlled trials have shown that all the treatments (tafamidis, diflunisal, patisiran, and inotersen) are effective in the context of a clinical trial. However, we have very little idea of whether individual patients will respond in an equally positive way to all the drugs or whether there will be some who respond better to one or another or not respond at all, nor do we know whether combinations will be additive or synergistic. We lack validated markers of clinical response. While the small molecule TTR stabilizers increase serum TTR levels, the RNA-based drugs lower serum TTR. In the latter case, it is not clear that the reduction in serum TTR is related to the clinical response in a 1:1 fashion. Pharmaceutical companies have made substantial investments in the development of these agents and will clearly attempt to recoup those investments quickly. It is incumbent upon those of us who care for these patients to develop ways to assess the effects of therapy in the shortest possible time at the lowest possible cost. The better we are able to accomplish this the more likely it is that we will be able to treat the most patients in the most clinically efficient fashion regardless of their economic status. We now have the drugs we just have to figure out who should get them and when.

Background: Hereditary transthyretin amyloidosis (ATTR) is a multisystemic disease involving mainly the peripheral nervous system and the heart. Liver transplantation (LT) is the reference treatment for ATTR neuropathy and preoperative detection of high risk patients is crucial. We aimed to document the causes of death of ATTR patients after LT, their temporal trends, and to evaluate whether the available preoperative tools that predict the risk of death after LT for hereditary ATTR amyloidosis matched with these trends. Methods: A retrospective longitudinal cohort study was performed on 215 consecutive ATTR patients who underwent LT between January 1993 and January 2011. Each patient’s death cause and timing were classified. Results: Over a median follow up of 5.9 years, 84 patients died. The rate of death was higher in the first year following LT than thereafter (13.0 vs. 4.3 ± 1.8%/year; p = .004). Cardiac events ranked as the leading cause of death (C: 38%), followed by infections (I: 24%), graft complications (G: 17%), end stage amyloidosis, stroke and others (ASO: 7% each). Deaths due to graft complications and infections (GI) occurred earlier than those due to end stage amyloidosis and stroke. Death prediction was less accurate for GI-related mortality than for other causes, which blunted the accuracy of the early-term risk prediction scores. Conclusions In ATTR amyloidosis, cardiac events were the leading cause of death after liver transplantation. Close preoperative evaluation allowed for accurate mid-term prediction of mortality, but the high rate of graft complications and infections blunted the early-term risk prediction.

Hereditary transthyretin (ATTR, ATTRm) amyloidosis, which is also called transthyretin-type familial amyloid polyneuropathy (ATTR-FAP), is a life-threatening, autosomal dominant systemic amyloidosi...

In the early stages of transthyretin familial amyloid polyneuropathy (TTR-FAP), clinical diagnosis is often difficult with fluctuations of subtle and non-specific symptoms [1,2]. It is important to...

Organ scarcity in the field of transplantation resulted into the idea of living related organ donation. Since hereditary (familial) amyloid polyneuropathy (FAP) usually results in a symptomatic phe...

Transthyretin hereditary (familial) amyloid polyneuropathy (TTR-FAP) is an irreversible, fatal, and rare autosomal dominant genetic disease characterized by progressive polyneuropathy due to amyloi...

Destructive arthropathy, which is called Charcot’ joint, occasionally develops in FAP patients in an advanced stage of the disease; it usually involves the knee or ankle joints due to marked sensor...

This is an electronic version of an article published in Amyloid 2010, Vol. 17, No. 1 : Pages 32-35. Amyloid is available online at: http://informahealthcare.com/doi/pdf/10.3109/13506121003619369, We report here two patients with amyloidogenic transthyretin (ATTR) Val30Met familial amyloid polyneuropathy (FAP) who developed numbness in both hands and were diagnosed as having bilateral carpal tunnel syndrome (CTS). In both patients systemic TTR amyloidosis consisting of polyneuropathy affecting both upper and lower limbs and/or autonomic dysfunction gradually appeared after surgery for CTS. Although CTS associated with TTR amyloidosis has been known as an initial symptom in some patients with ATTR non-Val30Met FAP and those with senile systemic amyloidosis, this is the first report of ATTR Val30Met FAP patients starting with upper limb neuropathy including CTS-like symptoms. It is also notable that both patients had no genealogical relationship with two Japanese endemic foci of this disease., Article, AMYLOID. 17(1):32-35 (2010)

There is accumulating evidence of the involvement of biological metal imbalance in the progression of amyloid diseases such as Alzheimer's, Parkinson's and prion diseases. However, the mineral status in patients affected with familial amyloidotic polyneuropathy (FAP) has not been investigated. It is the aim of this study to determine the metal concentrations in the serum and in the transthyretin (TTR) amyloid fibrils of FAP amyloidogenic TTR (ATTR) V30M patients. Multi-elemental analysis of 17 metals by high-resolution inductively coupled plasma mass spectrometry (ICP-MS) revealed a significant decrease of the metals Fe, Cu, Zn, Cs and Ba in the serum of FAP patients (mean age 38.5 +/- 8.3 years; duration of disease 4 +/- 2.6 years) in comparison with that of healthy individuals (mean age 36.2 +/- 9.2 years). On the other hand, these metals, except Cs, were found at high levels in the amyloid fibrils of FAP patients (mean age 55.8 +/- 9.2; duration of disease 6.5 +/- 1.3 years) compared with other metals. These findings firstly suggest that the mineral status could be a candidate factor, which participates in the wide spectrum of clinical pictures of FAP patients.

We present two families, from Spain and Portugal, with familial amyloid polyneuropathy (FAP) associated with the mutation TTRSer50Arg. This mutation was first described in two Japanese patients from independent families and later in a French-Italian patient and a Vietnamese family. The two families presented here, are the first to be diagnosed with this mutation in the Iberian Peninsula. In the patients of both families, FAP was very aggressive as they rapidly developed multiple symptoms with progressive deterioration; we emphasize the presence of severe orthostatic hypotension in the Spanish proband which confined him to a wheelchair. This proband was the first patient with this mutation to have undergone liver transplantation and results were encouraging. The mutation was detected in four patients and one disease-free relative by DNA sequencing of exon 3 and induced mutation restriction analysis. The most outstanding feature was the single base transversion A to C in codon 50 (CGT instead of AGT), whereas in both Japanese patients and the French-Italian patient it was T to G (AGG instead of AGT). To our knowledge only six FAP mutations with more than one single nucleotide mutation for the same codon have been reported to date.

Hereditary transthyretin (ATTR) amyloidosis is a systemic amyloidosis caused by mutant TTR and classified into familial amyloid polyneuropathy (ATTR-FAP), familial amyloid cardiomyopathy, and famil...

Familial amyloid polyneuropathy (FAP) manifests itself as a fiber-length-dependent polyneuropathy predominantly affecting sensory and autonomic nervous systems. Endoneurial amyloid deposits can be noxious to nerve fibers in several ways including mechanical and toxic effects on nerve fibers, and impairment of blood supply. On teased fiber preparations, a mixture of axonal degeneration and a lower proportion of segmental demyelination is observed. Within a few years of the first symptoms there is a near complete disappearance of myelinated and unmyelinated nerve fibers in the nerve samples taken by biopsy. On teased fiber preparations, amyloid deposits induce distortion, demyelination and eventually distal axonal degeneration of neighboring nerve fibers. This "mechanical" effect is associated with a "toxic" effect of amyloid fibrils leading to the disappearance of the basal lamina of Schwann cells, followed by death, presumably by apoptosis. Amyloid deposits often cluster around endoneurial blood vessels, and even invade their wall with subsequent occlusion of endoneurial vessels themselves.

We report an autopsy study of late-onset familial amyloid polyneuropathy with a variant transthyretin Val30Met in 2 brothers living in Kyoto, Japan. The disease onsets were at 64 and 59 years, and they died at 71 and 74 years old, respectively. They exhibited almost the same postmortem findings. Amyloid deposition was remarkable in the hearts, but was not seen in the renal glomeruli. In the peripheral nervous system, amyloid deposition was most prominent in the nerves immediately caudal to ganglia, moderate in the dorsal and sympathetic ganglia, and mild in the spinal roots, sciatic nerves, and distal nerves. The difference between the amyloid deposition in the proximal portion and distal portion of the extremity nerves appeared to be greater in the late-onset type than in the ordinary type, and this proximal deposition of amyloid may have induced severe distal nerve fiber degeneration.

Transthyretin familial amyloid polyneuropathy is characterized by a devastating sensory-motor polyneuropathy associated with life-threatening autonomic disturbance. An early diagnosis is mandatory to increase the chance to modify the course of the disease. This paper underlines the diagnostic problems encountered in this condition.

Transthyretin (TTR) Val30Met-associated familial amyloid polyneuropathy (FAP ATTR Val30Met) is the most common form of FAP. We compared the clinicopathological features and natural history of late-onset FAP ATTR Val30Met cases from non-endemic areas of Japan with early-onset cases from endemic foci. The characteristics of early-onset cases from endemic foci of Japan included the presence of sensory dissociation and marked autonomic dysfunction associated with a predominant loss of small-diameter myelinated and unmyelinated nerve fibers. These characteristics were not common in the late-onset cases from non-endemic areas. The distribution and characteristics of amyloid deposits in late-onset cases were similar to those of senile systemic amyloidosis with wild-type TTR deposition. The causal mechanism of differences between the early- and late-onset forms of FAP with the same mutation in the TTR gene has not yet been determined.

Gastrointestinal symptoms are frequent in familial amyloid polyneuropathy, mainly resulting from autonomic nervous system involvement. Dysphagia is one of the possible symptoms, although rarely severe or sudden. We describe a case of a sudden onset and severe dysphagia, a rare form of presentation, in a patient whose polyneuropathy was still beeing investigated and turned out to be ATTRVal30Met-polyneuropathy.

Familial amyloid polyneuropathy (FAP) is associated with massive endoneurial and extracellular deposition of amyloid, which is formed from a mutated transthyretin (TTR) protein. Ninety percent of TTR protein is produced in liver. Liver transplantation (LT) is the only treatment that can halt FAP clinical progression.We studied 35 LT patients. The mean age of the first symptoms was 36.6 years (ranging from 27 to 56), 19 were males, and 16 females, they underwent LT after a mean time of 5 years of symptomatic disease. Fifteen patients followed for more than 24 months after LT had periodic evaluations with clinical and neurophysiological scores (CS and NS). Ten were first evaluated before LT (mean follow-up time of 44 months after LT), and 5 were evaluated only after LT (for a mean time of 41 months). Five patients were followed periodically before LT (mean time of 44 months) to study the natural course of this condition.The mortality rate was of 14% in the first 6 months and was related to known complicatio...

The aim of the study was to evaluate hemodynamic responses after tilt reversal in familial amyloid polyneuropathy (FAP). Systolic blood pressure (BP) and heart rate variability (HRV) were analyzed ...

In order to define clinical patterns of light-chain amyloid (AL) polyneuropathy, we reviewed the data of 24 patients. At diagnosis, the mean duration of the symptoms was 21 months (range,...

A matrix-assisted laser desorption ionization/time-of-flight (MALDI/TOF) mass spectrometry (MS) system was used to detect variant transthyretin (TTR) in immunoprecipitated serum TTR molecules obtained from 6 patients with familial amyloid polyneuropathy (FAP) who were already proven not to have ATTR Val30Met. This simple and quick method showed six different patterns of mass spectra of TTR-related immunoprecipitates from these patients, and in each patient the clearly identified characteristic doublet-shaped ion peaks consisted of normal and variant TTR apart from each other peak with a mass difference between them. DNA sequencing confirmed that the patterns of variant TTR corresponded respectively to ATTR Val30Leu, ATTR Phe33Val, ATTR Asp38Ala, ATTR Ser50Arg, ATTR Ala97Gly and ATTR Ala97Ser. ATTR Asp38Ala and ATTR Ala97Ser are previously unknown variants of TTR leading to the development of FAP. ATTR Phe33Val was found in a Chinese FAP patient and ATTR Ala97Ser in a Taiwanese. Serum analysis using immunoprecipitation and MALDI/TOF MS system can provide useful information when investigating FAP patients with diverse types of variant TTR.

A transthyretin (TTR)-adsorption column has been developed for the removal of variant TTR from the plasma of patients with familial amyloid polyneuropathy (FAP). The adsorbent is an ion-exchange resin made of porous beads of polyvinyl alcohol gel covalently bound with dimethylaminoethanol. This column was used for three patients with type I FAP. It reduced the concentrations of both normal and variant TTR in the plasma to about half of their pre-adsorption levels. Except for thyroxine, retinol-binding protein and IgM, other proteins in serum were not significantly decreased and there were no adverse effects in long term clinical usage of this TTR-adsorption column. In this trial, we did not obtain concrete evidence that TTR-adsorption therapy can stop or delay the progression of the disease in a FAP patient. However, if we are able to apply this technique more frequently and effectively, TTR-adsorption therapy using our column might be useful for the treatment of FAP patients.

A clinical study and the analysis of transthyretin (TTR) abnormality were performed on a family with familial amyloid polyneuropathy (FAP) that had recently been found in China. Fourteen members over four generations were affected and their clinical pictures were consistent with those of type I FAP Using a matrix-assisted laser desorption ion-izatiod time- oS-flight mass spectrometry system, a TTR variant which possibly corresponded to Met 30 TTR was easily identified in the sera of patients and then, Met 30 TTR gene abnormality was confirmed on PCR-RFLP analysis. It is suggested that mass spectrometry system is a useful procedure for screening variant TTRs in the sera of large populations.

A clinicopathological study and transthyretin (TTR) gene analysis were performed on two families with familial amyloid polyneuropathy (FAP) that had recently been found in Argentina. One family originated in Portugal and the other in France/Spain. Patients suffered from sensorimotor polyneuropathy with autonomic dysfunction, and the TTR gene abnormality (Val 30→Met) was confirmed in both families. TTR-related FAP is more widely distributed than previously recognized.

The First International Workshop on liver transplantation in patients with familial amyloid polyneuropathy (FAP) was held at Huddinge Hospital in Stockholm, Sweden, September 10–11, 1993. Information was presented on 64 liver transplant recipients treated at 15 centers in 10 countries. Twenty-two patients had a follow-up time of more than 12 months, the longest follow-up was 41 months. Fifty-three patients had survived the procedure, while 11 had died within 8 months after the operation. The 1 and 2 year actuarial patient survival rate was 67 per cent. In most of the 22 patients surviving more than 1 year, the neurological symptoms had stabilized and the beneficial effect was most apparent as regards symptoms from the autonomic nervous system. There was consensus among the participants at the Workshop that liver transplantation for FAP is a worthwhile procedure and that such transplantation activities should continue. Transplantation should preferably be performed before the symptoms become severe and whi...

Proximal dominant muscle weakness and macroglossia, which appear in myopathy, are quite rare in transthyretin (TTR)-related familial amyloid polyneuropathy (FAP). We describe a patient with a novel...

Homozygotic cases of familial amyloid polyneuropathy (FAP) are expected to show late onset and mild clinical manifestations, although a homozygote case of FAP showing extremely early onse...