Familial Amyloid Polyneuropathy Type Research Articles

Detection of TTR Amyloid in the Conjunctiva Using a Novel Fluorescent Ocular Tracer.

Transthyretin amyloidosis (ATTR) is a significant cause of cardiomyopathy and other morbidities in the elderly and Black Americans. ATTR can be treated with new disease-modifying therapies, but large shortfalls exist in its diagnosis. The objective of this study was to test whether TTR amyloid can be detected and imaged in the conjunctiva using a novel small-molecule fluorescent ocular tracer, with the implication that ATTR might be diagnosable by a simple eye examination. Three approaches were used in this study. First, AMDX-9101 was incubated with in vitro aggregated TTR protein, and changes in its excitation and emission spectra were quantified. Second, a cadaver eye from a patient with familial amyloid polyneuropathy type II TTR mutation and a vitrectomy sample from an hATTR patient were incubated with AMDX-9101 and counterstained with Congo Red and antibodies to TTR to determine whether AMDX-9101 labels disease-related TTR amyloid deposits in human conjunctiva and eye. Last, imaging of in vitro aggregated TTR amyloid labeled with AMDX-9101 was tested in a porcine ex vivo model, using a widely available clinical ophthalmic imaging device. AMDX-9101 hyper-fluoresced in the presence of TTR amyloid in vitro, labeled TTR amyloid deposits in postmortem human conjunctiva and other ocular tissues and could be detected under the conjunctiva of a porcine eye using commercially available ophthalmic imaging equipment. AMDX-9101 enabled detection of TTR amyloid in the conjunctiva, and the fluorescent binding signal can be visualized using commercially available ophthalmic imaging equipment. AMDX-9101 detection of TTR amyloid may provide a potential new and noninvasive test for ATTR that could lead to earlier ATTR diagnosis, as well as facilitate development of new therapeutics.

A low amyloidogenic E61K transthyretin mutation may cause familial amyloid polyneuropathy.

Patients with transthyretin (TTR)-type familial amyloid polyneuropathy (FAP) typically exhibit sensory dominant polyneuropathy and autonomic neuropathy. However, the molecular pathogenesis of the neuropathy remains unclear. In this study, we characterize the features of FAP TTR the substitution of lysine for glutamic acid at position 61 (E61K). This FAP was late-onset, with sensory dominant polyneuropathy, autonomic neuropathy, and cardiac amyloidosis. Interestingly, no amyloid deposits were found in the endoneurium of the four nerve specimens examined. Therefore, we examined the amyloidogenic properties of E61K TTR in vitro. Recombinant wild-type TTR, the substitution of methionine for valine at position 30 (V30M) TTR, and E61K TTR proteins were incubated at 37°C for 72hr, and amyloid fibril formation was assessed using the thioflavin-T binding assay. Amyloid fibril formation by E61K TTR was less than that by V30M TTR, and similar to that by wild-type TTR. E61K TTR did not have an inhibitory effect on neurite outgrowth from adult rat dorsal root ganglion (DRG) neurons, but V30M TTR did. Furthermore, we studied the sural nerve of our patient by terminal deoxynucleotidyl transferase dUTP nick end labeling and electron microscopy. A number of apoptotic cells were observed in the endoneurium of the nerve by transferase dUTP nick end labeling. Chromatin condensation was confirmed in the nucleus of non-myelinating Schwann cells by electron microscopy. These findings suggest that E61K TTR is low amyloidogenic, in vitro and in vivo. However, TTR aggregates and amyloid fibrils in the DRG may cause sensory impairments in FAP because the DRG has no blood-nerve barrier. Moreover, Schwann cell apoptosis may contribute to the neurodegeneration.

Motor excitability measurements in early stage familial amyloid polyneuropathy: The influence of tafamidis treatment

To test motor fiber excitability in early affected patients with transthyretin (TTR)-type familial amyloid polyneuropathy (TTR-FAP) before and during tafamidis treatment. We examined the left median nerve of 21 healthy-matched controls and 10 early affected TTR-FAP patients using the automated threshold-tracking program, QTRAC. TTR-FAP patients were tested one day before the initiation of tafamidis treatment, 3 and 6 months later. The drug was well-tolerated in all patients; there was no drop-out. No statistical difference was found between healthy controls and TTR-FAP patients at study entry. On treatment, both stimulus intensity for 50% of the maximal motor response and rheobase increased significantly from entry to the last evaluation at 6 months (P<0.05). Strength duration time constant decreased significantly from the 3rd to the 6th month of evaluation (P<0.05). There was also a "fanning-out" effect on the late depolarization phase (TEd 90-100ms) as well as a shortened relative refractory period from study entry to the 6th month of evaluation. Threshold-tracking of median nerve motor fibers is not a helpful technique for the early diagnosis of TTR-FAP patients. Tafamidis was well-tolerated. We observed possible membrane hyperpolarization during treatment. Threshold tracking can contribute to documenting the action of new drugs to treat neuropathies. Tafamidis may change nerve electrical properties by reducing the burden of amyloid fibrils.

Ocular Manifestations and Therapeutic Options in Patients with Familial Amyloid Polyneuropathy: A Systematic Review.

Purpose. This paper aims to review the morphological and functional characteristics of patients affected by familial amyloid polyneuropathy (FAP), with greater focus on type I and its progression after liver transplantation. We also analyse therapeutic options for the ophthalmic manifestations. Methods. The literature from 2002 through 2015 was reviewed, with a total of 45 articles studied, using the key terms related to amyloidosis and its therapeutic approaches. Information was collated, evaluated, critically assessed, and then summarised in its present form. Pathophysiology and Treatment. FAP results from mutation of the transthyretin gene, with Val30Met being the most frequent substitution. The symptoms are those typical of a sensorimotor autonomic neuropathy and can be halted with liver transplantation. Nowadays there are new medical therapies that delay the progression of the systemic neuropathy. However, there are still no options to avoid ocular disease. Conclusion. The main ocular manifestations in patients with FAP type I are amyloid deposition in the vitreous, dry eye, and secondary glaucoma. Despite liver transplantation, eye synthesis of amyloid persists and is associated with progressive ocular manifestations, which require continued ophthalmologic follow-up. New therapeutic strategies are therefore needed, particularly to target the ocular synthesis of the abnormal protein.

Ophtalmologic changes in transthyretin familial amyloid polyneuropathy (ATTR-FAP)

Background Familial amyloid polyneuropathy (FAP) is an inherited disorder with autosomal dominant transmission and multiple phenotypes, characterized by systemic accumulation of amyloid fibrils. The most common type of FAP is related to a mutant transthyretin (TTR). TTR is mainly synthesized in the liver, but few amount of TTR is produced in the eye, namely in retinal pigment epithelium, which explains the continuous intra-ocular amyloid deposition observed in patients submitted to liver transplantation. The incidence of ophthalmic manifestations related to FAP depends on mutation involved, geographical area of patient and time of evolution of the disease. More than 100 mutations of TTR have been described but the most frequent in Portugal is TTR Val30Met. Even the same population with the same mutation can present significant clinical variability. TTR Met30Val FAP patients have different phenotypes according to their age at onset of the disease.

Bullous formation in a patient with familial amyloid polyneuropathy type I

Bullous formation in a patient with familial amyloid polyneuropathy type I

Severe heart disease in an unusual case of familial amyloid polyneuropathy type I

Familial amyloid polyneuropathy type I (FAP type I) is a rare hereditary systemic amyloidosis caused by the Val30Met mutation in the transthyretin (TTR) gene. The clinical onset and spectrum are variable and depend on phenotypic heterogeneity. Cardiac complications (dysrhythmias and conduction disturbances, cardiomyopathy and dysautonomia) indicate a poor prognosis, even after liver transplantation. We report an atypical case of FAP type I, highlighting the severe cardiac involvement and its complications.Early diagnosis of amyloid heart disease is increasingly important in the context of several clinical trials of promising new and experimental drugs.

Severe heart disease in an unusual case of familial amyloid polyneuropathy type I

Familial amyloid polyneuropathy type I (FAP type I) is a rare hereditary systemic amyloidosis caused by the Val30Met mutation in the transthyretin (TTR) gene. The clinical onset and spectrum are variable and depend on phenotypic heterogeneity. Cardiac complications (dysrhythmias and conduction disturbances, cardiomyopathy and dysautonomia) indicate a poor prognosis, even after liver transplantation. We report an atypical case of FAP type I, highlighting the severe cardiac involvement and its complications.Early diagnosis of amyloid heart disease is increasingly important in the context of several clinical trials of promising new and experimental drugs.

Pituicytoma with Gelsolin Amyloid Deposition

Pituicytoma is a rare low-grade (WHO grade I) sellar region glioma. Among sellar tumors, pituitary adenomas, mainly prolactinomas, may show amyloid deposits. Gelsolin is a ubiquitous calcium-dependent protein that regulates actin filament dynamics. Two known gene point mutations result in gelsolin amyloid deposition, a characteristic feature of a rare type of familial amyloid polyneuropathy (FAP), the Finnish-type FAP, or hereditary gelsolin amyloidosis (HGA). HGA is an autosomal-dominant systemic amyloidosis, characterized by slowly progressive neurological deterioration with corneal lattice dystrophy, cranial neuropathy, and cutis laxa. A unique case of pituicytoma with marked gelsolin amyloid deposition in a 67-year-old Chinese woman is described. MRI revealed a 2.6-cm well-circumscribed, uniformly contrast-enhancing solid sellar mass with suprasellar extension. Histologically, the lesion was characterized by solid sheets and fascicles of spindle cells with slightly fibrillary cytoplasm and oval nuclei with pinpoint nucleoli. Surrounding brain parenchyma showed marked reactive piloid gliosis. Remarkably, conspicuous amyloid deposits were identified as pink homogeneous spherules on light microscopy that showed apple-green birefringence on Congo red with polarization. Mass spectrometric-based proteomic analysis identified the amyloid as gelsolin type. Immunohistochemically, diffuse reactivity to S100 protein and TTF1, focal reactivity for GFAP, and no reactivity to EMA, synaptophysin, and chromogranin were observed. HGA-related mutations were not identified in the tumor. No recurrence was noted 14 months after surgery. To the knowledge of the authors, amyloid deposition in pituicytoma or tumor-associated gelsolin amyloidosis has not been previously described. This novel finding expands the spectrum of sellar tumors that may be associated with amyloid deposition.

Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascade

The transthyretin amyloidoses (ATTR) are invariably fatal diseases characterized by progressive neuropathy and/or cardiomyopathy. ATTR are caused by aggregation of transthyretin (TTR), a natively tetrameric protein involved in the transport of thyroxine and the vitamin A-retinol-binding protein complex. Mutations within TTR that cause autosomal dominant forms of disease facilitate tetramer dissociation, monomer misfolding, and aggregation, although wild-type TTR can also form amyloid fibrils in elderly patients. Because tetramer dissociation is the rate-limiting step in TTR amyloidogenesis, targeted therapies have focused on small molecules that kinetically stabilize the tetramer, inhibiting TTR amyloid fibril formation. One such compound, tafamidis meglumine (Fx-1006A), has recently completed Phase II/III trials for the treatment of Transthyretin Type Familial Amyloid Polyneuropathy (TTR-FAP) and demonstrated a slowing of disease progression in patients heterozygous for the V30M TTR mutation. Herein we describe the molecular and structural basis of TTR tetramer stabilization by tafamidis. Tafamidis binds selectively and with negative cooperativity (K(d)s ~2 nM and ~200 nM) to the two normally unoccupied thyroxine-binding sites of the tetramer, and kinetically stabilizes TTR. Patient-derived amyloidogenic variants of TTR, including kinetically and thermodynamically less stable mutants, are also stabilized by tafamidis binding. The crystal structure of tafamidis-bound TTR suggests that binding stabilizes the weaker dimer-dimer interface against dissociation, the rate-limiting step of amyloidogenesis.

Uma causa rara de hipertensão arterial secundária

A RARE CAUSE OF SECONDARY ARTERIAL HYPERTENSION Introduction: Familial amyloid polyneuropathy (FAP) type 1, better known in Portugal as "Doença dos Pezinhos", is a heredita- ry form of amyloidosis caused by the accumulation of a mutant protein (transthyretin). It is a rare disease which may be diffi- cult to diagnose when there is no previous family history of the condition. Case description: This report describes the case of a 60-year-old Caucasian woman with a history of hypothyroidism, dyslipi- demia, hyperuricemia, mixed anxiety and depressive disorder, chronic venous disease of the legs and hypertension. In June 2009, she was seen for the first time by her new family doctor, with laboratory results that showed proteinuria. A 24-hour urine col- lection for microalbuminuria and a renal scan were obtained. A diagnosis of chronic renal failure was made. The patient was re- ferred for a nephrology consultation in a central hospital where additional tests were done to determine the cause of her ill- ness. In August 2010, she was hospitalised in the nephrology unit with rapidly progressive renal failure with nephrotic protei- nuria. A renal biopsy showed familial amyloidosis, Portuguese type (ATTR). She was then referred to the familial amyloid poly- neuropathy clinic in another hospital. Comment: This case report shows the importance of adequate investigation in a patient with arterial hypertension. It also shows how rare causes may be considered in common clinical syndromes.

Death Anxiety and Symbolic Immortality in Relatives at Risk for Familial Amyloid Polyneuropathy Type I (FAP I, ATTR V30M)

This study is an investigation of the impact of familial amyloid polyneuropathy type I (FAP I, ATTR V30M) on death anxiety and symbolic immortality. Templer and Drolet's scales were administered to 524 individuals: (1) 84 relatives at risk, (2) 92 relatives not at risk for FAP I; and (3) a control group (n = 348) with no known hereditary disease in their families. At-risk relatives had, on average, a higher score for death anxiety and a lower score for symbolic immortality, than either those not-at-risk or controls. There were no significant differences in scores on either measure for those not-at-risk versus controls. Being at risk increases death anxiety and threatens the sense of symbolic immortality and psychosocial wellbeing. This may be true for other serious hereditary disorders as well. Genetic counsellors should become familiar with these concepts, feel comfortable initiating discussions about death with their patients, and be able to identify and reinforce their patients' and family members' sense of symbolic immortality.

Diagnosis of familial amyloid polyneuropathy: wide-ranged clinicopathological features

Owing to the recent development of biochemical and molecular analyses, familial amyloid polyneuropathy (FAP) is not considered to be as rare as was previously thought. Transthyretin (TTR) Val30Met-associated FAP (FAP ATTR Val30Met) is the most common form of FAP. Although patients with FAP ATTR Val30Met had been considered to be concentrated in geographically restricted areas of Japan, Portugal and Sweden, a late-onset form of this type of FAP was discovered in non-endemic areas and revealed to be widely distributed throughout the world. Therefore, there is an increasing necessity to characterize the variability in the clinical, electrophysiological and histopathological features of this disease. Recent progress in the diagnostic techniques for FAP is described, focusing especially on those for FAP ATTR Val30Met. Clinical, electrophysiological and histopathological features in early-onset FAP ATTR Val30Met cases from endemic foci and those in late-onset cases from non-endemic areas in Japan are comparatively described. Patients with FAP ATTR Val30Met from endemic foci and those from non-endemic areas show different clinical, electrophysiological and histopathological features. As compared with the classic FAP phenotype, the clinicopathological features of patients from the non-endemic areas tend to be nonspecific. Awareness of the possibility of sporadic late-onset FAP ATTR Val30Met is needed at the time of the initial clinical and electrophysiological evaluation of neuropathy with an undetermined etiology to avoid a missed diagnosis.

Hereditary amyloidosis of the Finnish type in a German family: Clinical and electrophysiological presentation

Hereditary amyloidosis of the Finnish type (HAF, or familial amyloid polyneuropathy type IV) is an autosomal dominant disease that has been described most commonly in the Finnish population but has also been found in some other countries. Herein we report the first German family whose members suffer from this condition. There are no known Finnish ancestors. We performed clinical and electrophysiological examinations in 22 members of this family. All symptomatic family members suffered from facial palsy, and most of them had peripheral neuropathy. One patient had confirmed corneal lattice dystrophy. Additional symptoms were hypoglossal nerve involvement in 5 patients and oculomotor nerve palsy in 1 patient. The lips of all older patients appeared thickened. The causative G654A mutation in the gelsolin gene was found in all affected family members.

Familial amyloidotic polyneuropathy with muscle, vitreous, leptomeningeal, and cardiac involvement: Phenotypic, pathological, and MRI description

Familial amyloidotic polyneuropathy (FAN type 1) is a rare systemic disease that causes severe and disabling peripheral neuropathy. We describe the phenotypic, radiological, and pathological characteristics of a patient with familial amyloid polyneuropathy type 1 who had evidence of motor-sensory-autonomic neuropathy, ocular vitreous deposits, diffuse leptomeningeal involvement, and hypertrophic cardiomyopathy. Muscle involvement, an infrequently reported feature, was also observed. Early recognition of the disease has significant therapeutic implications.

Penetrance estimation of TTR familial amyloid polyneuropathy (type I) in Brazilian families

Familial amyloid polyneuropathy (FAP) type I is a severe autosomal dominant inherited neuropathy associated with mutations in the transthyretin (TTR) gene. Significant phenotypic variability is seen amongst families with distinct geographic origin, especially regarding penetrance and age of onset. The aim of this study was to estimate the penetrance of FAP in Brazilian families. Twenty-two distinct families were ascertained through genetically confirmed index cases and included in this study. Genealogical and clinical data were obtained from a total of 623 individuals, including 126 affected by FAP. In 15 families, TTR genotyping was performed in all available relatives (n = 86), after informed written consent. Seven families did not consent for genetic testing, but agreed to provide clinical and genealogical data. Penetrance was estimated using a previously described method based on survival analysis and corrected for ascertainment bias. Mean age of onset in our sample was 34.5 years, with a significant earlier onset in males (31.1 vs. 35.9, P < 0.0001). The penetrance of FAP in our sample was estimated as 83% (95% CI: 66-99) after 60 years. Our results provide new information on FAP in Brazilian patients and may be helpful in the genetic counseling of this population.

Epidemiology of familial amyloid polyneuropathy in Japan: Identification of a novel endemic focus

Familial amyloid polyneuropathy (FAP) is distributed worldwide with several endemic foci including two major foci in Japan. To elucidate a nationwide epidemiology of FAP in Japan. (i) We analyzed the data of FAP patients registered by the Ministry of Health, Labour, and Welfare, Japan, during 2003-2005. (ii) As Ishikawa prefecture was found to be a novel endemic focus, we examined 27 FAP patients in Ishikawa to characterize their clinical and genetic features in comparison with other endemic foci. (i) The prevalence of familial amyloidosis in Japan was estimated to be 0.87-1.1 per 1,000,000 persons. Nagano prefecture had the highest prevalence (11-15.5), followed by Kumamoto (10.1-10.3), and then Ishikawa (3.5-4.2). (ii) All the FAP patients in Ishikawa had transthyretin (TTR) type FAP; all the families had a TTR Val30Met mutation except one family with a Leu58Arg mutation. FAP with Val30Met mutation in Ishikawa was characterized by late onset, high penetrance, and moderate autonomic dysfunction. Ishikawa prefecture is the third endemic focus of FAP in Japan. FAP with TTR Val30Met mutation in Japan can be classified to (i) early-onset and endemic (Nagano and Kumamoto), (ii) late-onset and endemic (Ishikawa), and (iii) late-onset and non-endemic types.

Is familial amyloid polyneuropathy rare?

Familial amyloid polyneuropathy (FAP) is one type of hereditary generalized amyloidosis, initially showing polyneuropathy and autonomic dysfunction but with later involvement of many visceral organs. The disease is caused by a mutation in the transthyretin (TTR) gene, which produces an amyloidogenic variant form of TTR (ATTR), thus leading to the designation ATTR type FAP.1 Up to now, more than 100 mutations have been identified as a cause of the gene abnormality in this disease,2 but the substitution of methionine for valine at position 30 (ATTRVal30Met) is the most common one that causes the classic phenotype of FAP. With regard to the clinical concept of ATTR type FAP, the following features have been emphasized.3 The disease occurs mainly in four endemic areas (the Oporto area in Portugal, Skelleftea in Sweden, and Arao and Ogawa in Japan) where it is inherited as an autosomal dominant trait with equal sex distribution. The age at onset is the late 20s to early 40s and polyneuropathy is consistently associated with sensory dissociation; that is, pain and thermal sensations are predominantly affected at an early stage of the disease. Various autonomic dysfunctions, including severe …

Liver transplantation and anemia in familial amyloidosis ATTR V30M

Familial amyloid polyneuropathy type I (FAP-I) is caused by a mutant transthyretin (TTR V30M) produced by liver, and orthotopic liver transplantation (OLT) is a widely accepted treatment for stopping the major production of TTR V30M. Anemia affects 24.8% of symptomatic FAP-I patients with low erythropoietin (Epo) levels, suggesting a blockage of Epo-producing cells by local or circulating factors. To evaluate the putative toxicity effect of the mutant protein on Epo-producing cells and consequent Epo production, clinical and laboratory parameters of 20 FAP patients were collected before and after liver transplantation, analyzed and compared. Following OLT, the prevalence of anemia increased, with a significant decrease in transferrin saturation, but without significant change in ferritin. Serum Epo levels remained low after OLT and the observed to expected (O/E) Epo level ratio decreased even further after OLT (O/E < 0.8 rose to 70%). Despite the decrease in creatinine clearance (95.1 to 66.9 ml/min, p < 0.001), a similar median O/E Epo level was observed, independently of the presence of renal failure, excluding an important impact of renal failure on Epo production. The increase of anemia after OLT and the maintenance of a defective endogenous Epo production after liver transplantation excluded an inhibitory effect of the circulating TTR V30M on the Epo-producing cells.

Familial systemic amyloidosis associated with bilateral sensorineural hearing loss and bilateral facial palsies

The Finnish type of familial amyloid polyneuropathy due to variant gelsolin is a rare form of familial amyloidosis. The subtype was first described in 1969 and is characterized by progressive cranial neuropathies, corneal lattice dystrophy and distal sensorimotor dysfunction. It is extremely uncommon, with only two families known to be affected in the UK. We discuss the case of a 70-year-old woman who presented with bilateral facial nerve palsies, bilateral sensorineural hearing loss and Finnish type familial hereditary amyloidosis. A literature search of the Medline database (1966-2005) was performed, using the keywords 'amyloid', 'hearing loss' and 'facial palsy'; however, this association appears to be a novel finding. We review the current literature and discuss otorhinolaryngological presentations of amyloidosis.