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Hereditary transthyretin amyloidosis is a fatal autosomal dominant disorder characterized by deposition of transthyretin amyloid into the peripheral nervous system, heart, kidney, and gastrointestinal tract. Previous treatments using liver transplantation and small molecule stabilizers were not effective in stopping disease progression. Inotersen, a 2'-O-methyoxyethyl-modified antisense oligonucleotide, which acts by reducing the production of transthyretin, was recently demonstrated to improve disease course and quality of life in early hereditary transthyretin amyloidosis polyneuropathy in a 15-month Phase III study.

Carpal tunnel syndrome (CTS) is a nonspecific manifestation of hereditary ATTR amyloidosis (ATTRm). Amyloid deposition of wild-type TTR (WT-ATTR) has been found in transverse carpal ligament (TCL) in idiopathic CTS. We retrospectively studied a group of patients with ATTRm and CTS submitted to carpal tunnel release surgery (CTRS).From the nerve conduction studies performed in our Clinical Unit dedicated to hereditary amyloidosis between July 2009 and October 2013, we selected patients who fulfilled neurophysiological criteria for CTS, had been submitted to CTRS and whose TCL was available for pathology. Clinical registries were reviewed and amyloid detection in the ligaments was performed using Congo-red staining.We included 16 patients: three males (18.8%), mean age = 46.1 years old, all with V30M mutation. At the time of surgery, four patients were considered asymptomatic and 12 symptomatic carriers, five of them late-onset ATTRm (onset age50 years old). In all but one patient, the CTS preceded the polyneuropathy. Amyloid detection in the TCL was positive in 14 patients (87.5%).In most patients, CTS preceded or was contemporary to the polyneuropathy and amyloid detection in TCL was positive. The detection of amyloid in TCL may add specificity to CTS as an early manifestation of the disease but more studies are needed.

We report a case of wild type ATTR (ATTRwt) amyloidosis in an 81-year-old man with a positive family history of hereditary ATTR (ATTRv) amyloidosis.An 81-year-old man (Figure 1; V:7) presented with...

The patient was a 43-year-old Japanese man. At age 41, he underwent carpal tunnel release surgeries for bilateral carpal tunnel syndrome. At age 42, he began experiencing recurrent episodes of naus...

Amyloidosis is a multisystem disease involving tissue deposition of misfolded proteins resulting in organ dysfunction and is associated with significant morbidity and mortality. Recent amyloid ligh...

In hereditary ATTR amyloidosis with a transthyretin (TTR) V30M mutation, TTR-related amyloid deposition in the kidney is a common postmortem finding [1]. However, the predominant clinical manifesta...

Cardiac amyloidosis is an increasingly recognized cause of restrictive cardiomyopathy, associated with significant morbidity and mortality. Days alive and outside of hospital (DAOH) is an emerging ...

Inflammation is a hallmark of several neurodegenerative disorders including familial amyloid polyneuropathy (FAP). FAP is associated with extracellular deposition of mutant transthyretin (TTR), lea...

Familial amyloid polyneuropathy (FAP) is an autosomal dominant disease caused by mutations in transthyretin (TTR) gene. Over 100 TTR mutations have been described to date in patients with TTR amylo...

Hereditary transthyretin (ATTRm) amyloidosis is an autosomal-dominant disorder caused by mutations in TTR, characterized by systemic accumulation of amyloid fibrils in various organs and peripheral...

Patients with transthyretin (TTR) Y114C develop fatal lobular hemorrhage and rapidly progressive dementia that presents with cerebral amyloid angiopathy (CAA) [1,2]. Because TTR is produced by the ...

Hereditary transthyretin amyloidosis (hATTR) is an autosomal dominant systemic amyloidosis due to point mutations in the TTR gene (chr18q12.1), resulting in misfolded proteins. Although more than 1...

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

The Transthyretin Amyloidosis Outcomes Survey (THAOS) was established in December 2007 and is the largest ongoing, international, observational registry, enrolling subjects with transthyretin amylo...

Patients with hereditary transthyroid (ATTR) amyloidosis usually present neurological (peripheral and autonomic) and cardiologic manifestations, but may also present renal manifestations due to glo...

Thank you for the response to my comment on your article: “Early diagnosis of ATTR amyloidosis through targeted follow-up of identified carriers of TTR gene mutations” [1,2].I fail to see any discr...

Peripheral neuropathy is a common neurological disorder. There may be important differences and similarities in the diagnosis of peripheral neuropathy between North America (NA) and South America (SA). Neuromuscular databases were searched for neuropathy diagnosis at two North American sites, University of Kansas Medical Center and University of Texas Southwestern Medical Center, and one South American site, Federal Fluminense University in Brazil. All patients were included into one of the six major categories: immune-mediated, diabetic, hereditary, infectious/inflammatory, systemic/metabolic/toxic (not diabetic) and cryptogenic. A comparison of the number of patients in each category was made between North America and South America databases. Total number of cases in North America was 1090 and in South America was 1034 [immune-mediated: NA 215 (19.7%), SA 191 (18%); diabetic: NA 148 (13.5%), SA 236 (23%); hereditary: NA 292 (26.7%), SA 103 (10%); infectious/inflammatory: NA 53 (4.8%), SA 141 (14%); systemic/metabolic/toxic: NA 71 (6.5%), SA 124 (12%); cryptogenic: NA 311 (28.5%), SA 239 (23%)]. Some specific neuropathy comparisons were hereditary neuropathies [Charcot-Marie-Tooth (CMT) cases] in NA 246/292 (84.2%) and SA 60/103 (58%); familial amyloid neuropathy in SA 31/103 (30%) and none in NA. Among infectious neuropathies, cases of human T-lymphotropic virus type 1 (HTLV-1) neuropathy in SA were 36/141(25%), Chagas disease in SA were 13/141(9%) and none for either in NA; cases of neuropathy due to leprosy in NA were 26/53 (49%) and in SA were 39/141(28%). South American tertiary care centers are more likely to see patients with infectious, diabetic and hereditary disorders such as familial amyloid neuropathies. North American tertiary centers are more likely to see patients with CMT. Immune neuropathies and cryptogenic neuropathies were seen equally in North America and South America.

Histological proof remains the gold standard for the diagnosis of amyloidosis. Nuclear medicine imaging techniques are able to determine the amyloid load in the body. Currently, the best imaging modality is I-123-SAP scintigraphy. This modality has high sensitivity for detecting amyloid deposits in all amyloid subtypes. Involvement of liver and spleen can be visualized before clinical signs are present. The addition of single photon emission computed tomography improves the differentiation of overlying organs. However, I-123-SAP is not FDA approved. Its availability is limited to two centres in Europe. Furthermore, it is not suitable for imaging cardiac involvement of amyloidosis, due to movement, blood-pool content and lack of fenestrated endothelial in the myocardium. Phosphate derivates labelled with Tc-99m, are able to detect calcium compounds in cardiac amyloidosis. Finally, I-123-MIBG, an analogue of norepinephrine, can detect cardiac sympathetic innervation abnormalities as a consequence of amyloid deposits. Both these last techniques seem to be able to detect cardiac involvement before echocardiographic parameters are present. We illustrate the clinical use of these modalities with two patients with ATTR type amyloidosis.

Familial amyloidotic polyneuropathy type IV, or Gelsolin amyloidosis (GA), is a rare condition caused by G654A or G654T mutation in gelsolin gene at 9q32-34. Gelsolin seems essential in many processes, including inflammation, cell motility, neural recovery, apoptosis and even carcinogenesis. So far reported from many European countries, USA, Japan, Iran and Brazil, GA is probably still underdiagnosed. The typical diagnostic triad includes corneal lattice dystrophy, progressive bilateral facial paralysis and cutis laxa. Patients present with progressive cranial and peripheral neuropathy, eye symptoms, usually mild proteinuria, and cardiac conductive disturbances with age. Central nervous system symptoms are rare. Gelsolin amyloid collection in tissues is widespread. To date, treatment is symptomatic. Regular check-ups with ophthalmologist are recommended. Plastic surgery relieves the functional symptoms caused by facial paralysis and loose, hanging facial skin.

Tremendous scientific progress has been made in the history of hereditary amyloidosis since Corino Andrade brought attention to the transthyretin type of peripheral neuropathy in 1952. For transthy...

Recent progress in diagnostic techniques has revealed that hereditary transthyretin (ATTR) amyloidosis is widely prevalent in areas other than conventional endemic foci [1–3]. Peripheral neuropathy...

Transthyretin amyloidosis (ATTR) patients with the V30M mutation, who progress to end-stage renal disease (ESRD) are mostly female with later onset of neuropathy, usually after the sixth decade of ...

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 amyloidosis (ATTR) is a systemic form of amyloidosis associated with at least 130 genetic mutations in TTR. Most forms of ATTR are associated with neuropathy, but cardiomyopathy may b...

Familial amyloid polyneuropathy, Finnish type (FAF), is a dominantly inherited disorder caused by mutations in the gelsolin gene and rarely reported in several countries. We report a Japanese FAF patient with a missense mutation (G654A), presenting multiple cranial nerve symptoms, corneal lattice dystrophy, carpal tunnel syndrome and orthostatic hypotension. It is notable that this patient showed very wide range of cranial nerve involvement (III, IV, VI, VII, VIII, IX, X and XII), which have gradually deteriorated for 6 years. The patient also has carpal tunnel syndrome, which is not commonly found in FAF cases. Even if not for certain familial inheritance, it is preferable to take consideration of FAF as one of differential diagnoses of a case presenting multiple cranial nerves symptoms.

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 are more than a few risks of hemorrhage complication in patients with amyloidosis. Although most cases with amyloidosis exhibit minor bleeding manifestations, they can be occasionally associated with life-threatening problems. To our knowledge, there are only a few cases of spontaneous pericardial hematoma associated with amyloidosis. We here report a patient who suddenly died of cardiac tamponade with massive pericardial hematoma 7 years after the diagnosis of familial amyloid polyneuropathy (FAP). A 69-year-old female with FAP with cardiogenic shock was admitted to our emergency room. Although she previously underwent permanent pacemaker implantation for atrial fibrillation with slow ventricular response, electrocardiogram showed a critical pacing failure. Emergent telemetry check revealed a sudden extreme increase of pacing capture threshold in the right ventricle. Maximum pacing voltage could not improve the critical condition, and she died 7 h after arrival. Autopsy showed a massive pericardial hematoma in the right ventricular free wall, and microscopic examination revealed typical amyloid deposition in the arterial wall of the pericardium. In this case, it is assumed that a sudden rupture of fragile pericardial vessels with amyloid deposition led to the lethal pericardial hematoma.

Discordant expression of Familial Amyloid Neuropathy (FAP) in monozygotic twins is a rare event. Only five such cases have been described in the literature so far. We report the clinical, neurophysiologic and autonomic findings of Brazilian monozygotic twins discordant for the expression of FAP type I. Twin I first presented symptoms at the age of 21, when his brother was completely asymptomatic. Twin 2 only presented symptoms at the age of 25, almost four years after his brother. Both brothers eventually developed the complete phenotype of FAP type I. The occurrence of monozygotic twins discordant for the expression of FAP type I suggests that other factors beside TTR gene mutations should play an important role in the pathogenesis of this condition. Environmental factors, as well as modifier genetic loci are likely to modulate the expression of FAP type I and the study of cases such as the one presented here may help to identify some of these factors.

Clinical pictures of familial amyloid polyneuropathy (FAP) vary considerably, perhaps because of the many gene mutations of transthyretin (TTR), but even in patients having the most common mutation of TTR (the substitution of methionine for valine at position 30 (ATTRVal30Met)), the age of onset ranges from the late 20s to the early 60s. Although genetic anticipation has been considered to play a role in producing this wide range of ages of onset, the precise pathogenesis is incompletely understood. It has been experimentally shown that murine systemic AA and AApoAII amyloidoses can be transmitted by ingestion of amyloid fibrils themselves or amyloid-like pathological agents. In this study, we examined biopsied mammary glands obtained from three female ATTRVal30Met FAP patients who were of gestation age. Amyloid deposition was commonly seen in the glands and, in the two patients with apparent FAP symptoms, heavy deposits of amyloid surrounded many lactiferous alveoli and ducts, where some deposits of amyloid actually faced the central lumens. These findings raise the possibility that milk from FAP mothers contains ATTR-derived amyloid fibrils and/or fragments, which might be causally related to the development of genetic anticipation in this disease.

Liver transplantation for familial amyloid polyneuropathy (FAP) patients has been carried out worldwide and the outcomes seem to be promising. To clarify the severity of amyloid deposits on visceral organs, we evaluated the histopathological findings of biopsied renal and sural nerve specimens in 13 FAP patients with ATTR Val30Met by quantitative analysis, and compared them with the outcome of transplantation. Renal dysfunction with proteinuria seemed to correlate with the degree of amyloid deposits in glomeruli, not with that in medullary tissues. The severity of renal amyloid deposition did not consistently parallel that of myelinated nerve fiber loss in sural nerve. Three patients with proteinuria and severe amyloid deposits in glomeruli were considered to be unsuitable for transplantation. Ten patients underwent living donor liver transplantation and three resulted in unfavorable outcomes. These three had heavy amyloid deposits on renal tissues, especially in glomerular areas, but the severity of myelinated nerve fiber loss in their sural nerves was very similar to that in patients who made a good recovery. The prognosis after operation might be closely related to the severity of amyloid deposits in renal glomeruli. Renal biopsy is, therefore, recommended when determining the indications and contraindications for liver transplantation in FAP patients, although this biopsy is not routinely required.

Background: Cardiac amyloidosis had been considered to be an incurable disease; however, new disease-modifying therapeutic approaches have succeeded in ameliorating the disease. Therefore, early and precise diagnosis based on the amyloid precursor protein is extremely important.Objective: To determine the prevalence rates of systemic amyloidoses underlying cardiac amyloidosis.Methods: The types of amyloidosis in 53 consecutive patients with endomyocardial biopsy-proven cardiac amyloidosis were analyzed by Congo red and immunohistochemical staining. If staining for TTR was positive, direct DNA sequencing of the entire TTR gene was performed.Results: ATTR amyloidosis was the most common (32/53 patients, 60.4%). The ATTR amyloidosis subtypes were senile systemic amyloidosis (SSA) 11, familial ATTR 10, and genotype unknown 11. AL amyloidosis was the next most frequent (19/53, 35.8%).Conclusions: ATTR amyloidosis, especially SSA, might be much more common than previously thought. With the development o...

Acceleration of amyloid deposition by administration of amyloid fibrils and transmissibility of disease have been reported in several types of amyloidoses. Families with a variant transthyretin (TTR V30M)-associated familial amyloidotic polyneuropathy (FAP) exhibit genetic anticipation, with TTR V30M-amyloid depositing at an earlier age in successive generations. The molecular bases of anticipation in FAP have remained to be determined. We asked if administration of TTR-amyloid fibrils (ATTR) extracted from the heart of an FAP TTR V30M patient would accelerate ATTR deposition in transgenic mice expressing the human mutant ttr gene responsible for FAP TTR V30M and indeed the administration did accelerate deposition of apolipoprotein A-II-amyloid fibrils (AApoAII), and not A TTR. Our experiments present, for the first time, evidence that the degree of inducibility of ATTR is low relative to AApoAII and we suggest that administration of ATTR may not explain the genetic anticipation which occurs in FAP.

Most transthyretin (TTR) mutations lead to TTR amyloid depositions in patients with familial amyloidotic polyneuropathy and familial amyloidotic cardiomyopathy. However, though an amyloidogenic protein itself, TTR inhibits aggregation of Alzheimer's amyloid beta protein (A beta) in vitro and in vivo. The pathogenic relationship between two amyloidogenic processes remains unclear. To understand how TTR mutations influence the ability of TTR to inhibit A beta amyloidosis, forty-seven recombinant TTR variants were produced and analyzed. We showed that all recombinant proteins formed tetramers and were functional in thyroxine binding. Acid denaturation at pH 3.8 resulted in aggregation and fibril formation of all TTR variants. However, only TTR G42 and TTR P55 formed fibrils at pH 6.8. Most TTR variants bound to A beta and inhibited A beta aggregation in vitro. TTR variants S64, A71, Q89, V107, H114 and I122 revealed decreased binding to A beta and decreased inhibition of A beta aggregation. Only TTR G42 and TTR P55 completely failed to bind A beta and to inhibit A beta aggregation. We suggest that TTR variants characterized by decreased binding to A beta or by decreased inhibition of A beta aggregation in vitro may contribute to A beta amyloid formation in vivo. These TTR variants might be important targets for epidemiological studies in Alzheimer's disease.

Autopsy findings in a 68-year-old FAP patient with a homozygous mutation of the Val30Met TTR gene were described. In addition to amyloid deposits on the visceral organs, peripheral nerves and the vitreous body, severe deposition of amyloid in the leptomeninges and subarachnoid vessels in the brain and spinal cord was present. A double dose of the mutant gene may accelerate amyloid deposition on the ocular and meningeal tissues.

Liver transplantation for transthyretin (TTR) amyloidosis is today an accepted treatment for the disease. However, the long-term outcome of the procedure remains to be elucidated, especially for non-Val30Met TTR mutations. Using serum amyloid P (SAP) component scintigraphy, amyloid deposits have been shown to decrease in approximately 50% of the patients, but this finding has not been confirmed in biopsy specimens. However, free radical activity has been reduced after transplantation. Conflicting results regarding neurological disturbances have emerged, but some improvement may take place, especially in patients transplanted at an early stage of the disease. For heart complications, recent reports indicate that increased cardiomyopathy after transplantation is a common finding, and that the development of arrhythmia is also common. Even though an improvement of the patients' nutritional status is observed after transplantation, gastrointestinal disturbances appear to be unchanged after the procedure. Kidney function deteriorates initially after transplantation, but thereafter it remains stable. Since TTR is produced locally in the eye, development of amyloid deposits in the eye has been reported in several cases after transplantation. Transplantation for FAP should be performed early on after onset of the disease, since the majority of symptoms will remain unchanged after the procedure. The patients should be followed closely after transplantation to detect the development of heart arrhythmia.

Liver transplantation has been performed for patients with incurable liver diseases but this therapeutic technique can be extended to neurological disorders, such as familial amyloid polyneuropathy and adult-onset type II citrullinemia. An amyloid precursor in familial amyloid polyneuropathy, a variant form of transthyretin, is produced mainly in the liver. After liver transplantation, it has been shown that this amyloid precursor disappears from the sera of patients once progression of the disease has halted. Type II citrullinemia is caused by a deficiency of liver-specific argininosuccinate synthetase activity and shows various neurological manifestations closely resembling those of hepatic encephalopathy, resulting in fatal outcome. All metabolic abnormalities in this disease, which include elevated plasma concentrations of citrulline and ammonia, can be immediately corrected by liver transplantation.

Familial Amyloidotic Polyneuropathy (FAP) was initially classified into different types based on the clinical presentation. FAP Type I included patients with predominant upper limb neuropathy, while Type II patients had initial lower limb involvement. Further confusing the issue was the description of FAP Types III and IV, which proved to result from proteins other than Transthyretin (TTR). More recently, molecular classification has superseded clinical classification. It is increasingly clear that the clinical picture of patients with FAP is widely variable. Significant variation in the clinical presentation occurs between individual kindreds with the same mutation and even among family members. The factors that govern this variation are unknown at present. Some general principles have emerged from studying patients with different mutations. Leptomeningeal involvement is rare and occurs predominantly in only a few mutations. Isolated cardiac involvement in African-Americans is invariably associated with the V122I mutation. Given the variability in presentation, it is not possible to accurately classify patients on the basis of neuropathy, either sensorimotor or autonomic. Further, cardiac involvement, which occurs with increased frequency in non-V30M patients, is not a reliable phenotype to distinguish specific mutations. Molecular classification has become the gold standard for classification of the different forms of FAP. While some rare mutations confer a more predictable phenotype, the majority of the known mutations are associated with a wide variation in phenotype.

131 HA-TTR patients from a single referral centre presented at onset five major clinical syndromes: (1) the typical "Portuguese variant" axonal polyneuropathy with dissociated (syringomyelic like) sensory loss and autonomic dysfunction; (2) bilateral carpal tunnel syndrome; (3) restless leg syndrome with impotence and unexplained loss of weight; (4) pure motor neuropathy without autonomic abnormalities; (5) recurrent small brain or spinal cord ischemia or haemorrhages with leptomeningeal amyloid deposition (and late superficial siderosis of the central nervous system) and vitreous deposits. Some patients in our population presented a "pseudodemyelinating" onset of the somatic neuropathy, as well as atypical motor neuropathy simulating lower motor neuron disease. The five syndromes can overlap in advanced stages of the disease. Genetic screening of HA-TTR could be worthwhile in any idiopathic progressive axonal peripheral neuropathy, as well as in drug resistant demyelinating sensory-motor neuropathy or in pure motor neuropathy, when multi-organ involvement is present.

We designed a phase II, open-label study to evaluate the efficacy, tolerability, safety, and pharmacokinetics of orally doxycycline (100 mg BID) and tauroursodeoxycholic acid (TUDCA) (250 mg three times/day) administered continuously for 12 months. Primary endpoint is response rate defined as nonprogression of the neuropathy and of the cardiomyopathy. Since July 2010, we enrolled 20 patients. Seventeen patients have hereditary ATTR, two patients have senile systemic amyloidosis, and one is a domino recipient. Seven patients completed 12-month treatment, 10 completed 6-month treatment, two discontinued because of poor tolerability, and one is lost at follow-up. No serious adverse events were registered. No clinical progression of cardiac involvement was observed. The neuropathy (Neuropathy Impairment Score in the Lower Limbs [NIS-LL] and Kumamoto score) remained substantially stable over 1 year. These preliminary data indicate that the combination of Doxy-TUDCA stabilizes the disease for at least 1 year in the majority of patients with an acceptable toxicity profile.

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.

A 73-year-old man was admitted to our Department with a 12-month history of progressive weakness and sensory disturbances in all four limbs. He was the product of non-consanguineous healthy parents...

A Japanese case with familial amyloidotic polyneuropathy (FAP) associated with the transthyretin mutation Thr60Ala (Appalachian-type mutation) is described This is the first reported case of a non-Caucasian harboring this type of TTR mutation. The patient developed severe late-onset restrictive cardiomyopathy as well as sensorimotor and autonomic polyneuropathy, which were essentially similar to the previously reported clinical pictures of Appalachian-type FAP.

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,...

Familial amyloidotic polyneuropathy (FAP) is characterized by deposits of amyloid fibers in which the major protein component is transthyretin (TTR). Nearly fifty mutations have been reported for the TTR in hereditary FAP. Protein crystallography of mutant TTRs has shown that the molecular structures of the variant molecules are similar to those found in the wild type. On this basis, the FAP fibers were initially proposed to consist of native-like TTR tetramers. In the current paper, we used x-ray fiber diffraction to study the structure of FAP fibers from biopsy samples of vitreous humor and kidney. The reflections of the vitreous sample showed a cross-beta diffraction pattern. All the meridional reflections were indexed by a one-dimensional, 29 A-period lattice, and the equatorial reflections were indexed by an apparent one-dimensional 67 A-period lattice. The x-ray intensity distribution indicated that the unit structure, which is similar to a TTR monomer, is composed of a pair of beta-sheets consisting of four hydrogen-bonded beta-chains per sheet, with the beta-chains oriented approximately normal to the fiber axis. The axial disposition of these units, with a 29 A-period, constitutes the protofilament; and a tetrameric lateral assembly of the protofilaments containing the core domain of the approximately 20 A-wide beta-sheet structure constitutes the FAP amyloid fiber. An inter-fiber separation of 75 A in these concentrated samples accounts for the apparent one-dimensional lattice perpendicular to the fiber axis. In the delipidated kidney FAP sample, the diffraction pattern indicated a pair of beta-sheets, suggesting that the protofilament structure in kidney is similar to that in vitreous humor. In the non-delipidated sample the successive sharp reflections indexed to a one-dimensional, 48.9 A-lattice, and the electron density projection showed a density elevation at the center of a lipid bilayer. This suggests that lipid may be associated with the monomeric TTR in the kidney FAP protofilament.

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...