Familial Amyloidotic Polyneuropathy Type Research Articles

On-Line Immunoaffinity Solid-Phase Extraction Capillary Electrophoresis-Mass Spectrometry for the Analysis of Serum Transthyretin.

The analysis of low abundant proteins in biological fluids by capillary electrophoresis (CE) is particularly problematic due to the typically poor concentration limits of detection of microscale separation techniques. Another important issue is sample matrix complexity that requires an appropriate cleanup. Here, we describe an on-line immunoaffinity solid-phase extraction capillary electrophoresis-mass spectrometry (IA-SPE-CE-MS) method for the immunoextraction, preconcentration, separation, detection, and characterization of serum transthyretin (TTR). TTR is a protein biomarker related to diverse types of amyloidosis, such as familial amyloidotic polyneuropathy type I (FAP-I), which is the most common hereditary systemic amyloidosis.

A chemometric approach for characterization of serum transthyretin in familial amyloidotic polyneuropathy type I (FAP-I) by electrospray ionization-ion mobility mass spectrometry

In this study, we describe a chemometric data analysis approach to assist in the interpretation of the complex datasets from the analysis of high-molecular mass oligomeric proteins by ion mobility mass spectrometry (IM-MS). The homotetrameric protein transthyretin (TTR) is involved in familial amyloidotic polyneuropathy type I (FAP-I). FAP-I is associated with a specific TTR mutant variant (TTR(Met30)) that can be easily detected analyzing the monomeric forms of the mutant protein. However, the mechanism of protein misfolding and aggregation onset, which could be triggered by structural changes in the native tetrameric protein, remains under investigation. Serum TTR from healthy controls and FAP-I patients was purified under non-denaturing conditions by conventional immunoprecipitation in solution and analyzed by IM-MS. IM-MS allowed separation and characterization of several tetrameric, trimeric and dimeric TTR gas ions due to their differential drift time. After an appropriate data pre-processing, multivariate curve resolution alternating least squares (MCR-ALS) was applied to the complex datasets. A group of seven independent components being characterized by their ion mobility profiles and mass spectra were resolved to explain the observed data variance in control and patient samples. Then, principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) were considered for exploration and classification. Only four out of the seven resolved components were enough for an accurate differentiation. Furthermore, the specific TTR ions identified in the mass spectra of these components and the resolved ion mobility profiles provided a straightforward insight into the most relevant oligomeric TTR proteoforms for the disease.

On-line immunoaffinity solid-phase extraction capillary electrophoresis mass spectrometry using Fab´antibody fragments for the analysis of serum transthyretin

This paper describes an on-line immunoaffinity solid-phase extraction capillary electrophoresis mass spectrometry (IA-SPE-CE-MS) method using an immunoaffinity sorbent with Fab′ antibody fragments (Fab′-IA) for the analysis of serum transthyretin (TTR), a homotetrameric protein (Mr~56,000) involved in different types of amyloidosis. The IA sorbent was prepared by covalent attachment of Fab′ fragments obtained from a polyclonal IgG antibody against TTR to succinimidyl silica particles. The Fab′-IA-SPE-CE-MS methodology was first established analyzing TTR standard solutions. Under optimized conditions, repeatability and reproducibility were acceptable, the method was linear between 1 and 25µgmL−1, limits of detection (LODs) were around 0.5µgmL−1 (50-fold lower than by CE-MS, ~25µgmL−1) and different TTR conformations were observed (folded and unfolded). The applicability of the developed method to screen for familial amyloidotic polyneuropathy type I (FAP-I), which is the most common hereditary systemic amyloidosis, was evaluated analyzing serum samples from healthy controls and FAP-I patients. For the analysis of sera, the most abundant proteins were precipitated with 5% (v/v) of phenol before Fab′-IA-SPE-CE-MS. The current method enhanced our previous results for the analysis of TTR using intact antibodies immobilized on magnetic beads. It allowed a slight improvement on LODs (2-fold), the detection of proteoforms found at lower concentrations and the preparation of microcartridges with extended durability.

Comparison of capillary electrophoresis and capillary liquid chromatography coupled to mass spectrometry for the analysis of transthyretin in human serum

Capillary electrophoresis and capillary liquid chromatography coupled to mass spectrometry (CE-MS and CapLC–MS, respectively) are nowadays very suitable techniques for the separation and characterization of intact proteins in biological fluids. In this paper, we compare the performance of both techniques for the analysis of transthyretin (TTR), which is a homotetrameric protein (relative molecular mass (Mr) ∼56,000) involved in different types of amyloidosis. Furthermore, it is also presented a novel sample pretreatment based on immunoprecipitation (IP) using Protein A Ultrarapid Agarose™ (UAPA) magnetic beads (MBs) to purify TTR from serum samples. This novel IP based on MBs allowed the detection of TTR monomeric proteoforms that were not possible to analyze by conventional IP in solution. In addition, UAPA MBs provided many other desirable advantages including higher selectivity and minimal unspecific binding of other proteins. CE-MS and CapLC–MS were applied to analyze serum samples from healthy controls and familial amyloidotic polyneuropathy type I (FAP-I) patients, who suffered from the most common hereditary systemic amyloidosis. Both techniques allowed detecting the same TTR proteoforms, including the mutant TTR (Met 30) variant (variation in relative molecular mass (ΔMr) was +32.07, from wild-type TTR). Migration/retention times and relative quantitation of the different proteoforms were similar and reproducible in both cases, but the limits of detection (LODs) achieved by CE-MS were slightly lower (2–2.5-fold). Some other differences were also found on separation selectivity (migration orders and separation of antibody), peak efficiency, total analysis time, calibration ranges and experimental Mr accuracy.

Analysis of serum transthyretin by on-line immunoaffinity solid-phase extraction capillary electrophoresis mass spectrometry using magnetic beads.

In this paper, an on-line immunoaffinity solid-phase extraction capillary electrophoresis mass spectrometry (IA-SPE-CE-MS) method using magnetic beads (MBs) is described for the analysis of serum transthyretin (TTR), which is a protein related to different types of amyloidosis. First, purification of TTR from serum was investigated by off-line immunoprecipitation and CE-MS. The suitability of three Protein A (ProA) MBs (Protein A Ultrarapid Agarose(TM) (UAPA), Dynabeads(®) Protein A (DyPA) and SiMAG-Protein A (SiPA) and AffiAmino Ultrarapid Agarose(TM) (UAAF) MBs to prepare an IA sorbent with a polyclonal antibody (Ab) against TTR, was studied. In all cases, results were repeatable and it was possible the identification and the quantitation of the relative abundance of the six most abundant TTR proteoforms. Although recoveries were the best with UAPA MBs, UAAF MBs were preferred for on-line immunopurification because Ab was not eluted from the MBs. Under the optimized conditions with standards in IA-SPE-CE-MS, microcartridge lifetime (>20 analyses/day) and repeatability (2.9 and 4.3% RSD for migration times and peak areas) were good, the method was linear between 5 and 25 μg/mL and LOD was around 1 μg/mL (25 times lower than by CE-MS, ≈25 μg/mL). A simple off-line sample pretreatment based on precipitation of the most abundant proteins with 5% (v/v) of phenol was necessary to clean-up serum samples. The potential of the on-line method to screen for familial amyloidotic polyneuropathy type I (FAP-I), which is the most common hereditary systemic amyloidosis, was demonstrated analysing serum samples from healthy controls and FAP-I patients.

The role of complement in ATTR amyloidosis: a new therapeutic avenue?

Background Familial Amyloidotic Polyneuropathy Type I is a lethal autosomal dominant sensorimotor and autonomic neuropathy due to deposition of amyloid fibrils composed of aberrant transthyretin (TTR) protein (ATTR neuropathy). A substitution of valine for methionine at position 30 of the protein is the commonest mutation. ATTRMet30 neuropathy exhibits a great degree of variability, both in the age of onset as well as penetrance among different populations. The penetrance in Cyprus is 28% compared to 2% and 80% in north Sweden and Portugal respectively. Genetic and epigenetic factors have been implicated and although we have previously demonstrated a correlation of complement C1q polymorphisms with age of onset among the Cypriot population, the exact mechanisms remain undetermined. The complement cascade, as a whole, has long been investigated for its association with inflammation and macromolecule aggregate clean-up. In the mouse model of Alzheimer disease, C1q has been shown to modulate beta-amyloid induced complement activation and neuronal loss. C1q has also been shown to be neuroprotective against toxic concentrations of serum amyloid P and to modulate phagocytosis of soluble pre-amyloid aggregates. Thus C1q appears to be strong candidate for being a modifier in the phenotype of ATTRMet30 neuropathy.

Characterisation of serum transthyretin by electrospray ionisation-ion mobility mass spectrometry: Application to familial amyloidotic polyneuropathy type I (FAP-I)

Transthyretin (TTR) is a homotetrameric protein which is known to misfold and aggregate causing different types of amyloidosis, such as familial amyloidotic polyneuropathy type I (FAP-I). FAP-I is associated with a specific TTR mutant variant (TTR (Met30)) that can be easily detected analysing the monomeric forms of the mutant protein. Meanwhile, the mechanism of protein aggregation onset, which could be triggered by structural changes on the native tetrameric protein complex, remains uncertain. We developed and described herein a new sample pretreatment based on immunoprecipitation (IP) to purify TTR from serum under non-denaturing conditions. Later, a nano-electrospray ionization-ion mobility mass spectrometry (nano-ESI-IM-MS or IM-MS) method was optimised to analyse the protein complexes in serum samples from healthy controls and FAP-I patients. IM-MS allowed separation and characterisation of tetrameric, trimeric and dimeric TTR gas ions due to their differential drift time, which is related to ion size and charge. The tetramer-to-dimer abundance ratio was differential between healthy controls and FAP-I patients (asymptomatic, symptomatic and an iatrogenic patient originally without the mutation who received a liver transplant from an FAP-I patient), and was also indicative of the effectiveness of liver transplantation as a treatment for FAP-I.

Analysis of transthyretin in human serum by capillary zone electrophoresis electrospray ionization time-of-flight mass spectrometry. Application to familial amyloidotic polyneuropathy type I.

Transthyretin (TTR) is known to misfold and aggregate, causing different types of amyloidosis. Familial amyloidotic polyneuropathy type I (FAP-I), which is the most common hereditary systemic amyloidosis, is associated with a TTR variant that presents a single amino acid substitution of valine for methionine at position 30 (Met 30). To screen for TTR-related amyloidosis rapidly and reliably, we have developed a novel procedure based on the analysis of monomers from the homotetrameric protein (∼56 kDa). First, we established a CZE-ESI-TOF-MS method to detect wild-type (normal) TTR with or without several PTMs, as well as an extra minor isoform in TTR standard solutions. Later, a sample pretreatment based on immunoprecipitation (IP) and centrifugal filtration was optimized to analyze serum samples from healthy controls and FAP-I patients (including an asymptomatic patient, a symptomatic patient, a liver-transplanted patient with the specific mutation, and a patient originally without the mutation who received a liver transplant from an FAP-I patient (iatrogenic FAP-I)). The mutant TTR (Met 30) variant with a relative molecular mass 32.07 higher than the wild-type TTR was found in the asymptomatic, the symptomatic and the iatrogenic FAP-I patients, who interestingly also presented the same concentration ratio between both variants of TTR (abnormal and normal). In contrast, as in the healthy controls, the abnormal TTR variant was not detected in the liver-transplanted patient with the specific mutation, which confirms the effectiveness of the treatment. The proposed procedure could be regarded as a suitable screening system for individuals with suspected TTR amyloidosis, and to gain insight into TTR structure, to understand the mechanism underlying the disease.

Dominant cardiac type of familial amyloidotic polyneuropathy associated with a novel transthyretin variant Thr59Arg

Muscle & NerveVolume 48, Issue 5 p. 839-841 Letter to the Editor Dominant cardiac type of familial amyloidotic polyneuropathy associated with a novel transthyretin variant Thr59Arg Konen Obayashi MD, PhD, Konen Obayashi MD, PhD Diagnostic Unit for Amyloidosis, Department of Laboratory Medicine, Kumamoto University Hospital, Kumamoto, JapanSearch for more papers by this authorYohei Misumi MD, PhD, Yohei Misumi MD, PhD Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, JapanSearch for more papers by this authorTetsuya Watanabe MD, Tetsuya Watanabe MD Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, JapanSearch for more papers by this authorTomotaka Ando MD, Tomotaka Ando MD Cardiovascular Division and Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, JapanSearch for more papers by this authorTakafumi Akagami MD, PhD, Takafumi Akagami MD, PhD Division of Coronary Heart Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, JapanSearch for more papers by this authorMasayoshi Tasaki MPAS, Masayoshi Tasaki MPAS Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, JapanSearch for more papers by this authorSatoru Shinriki DDSPhD, Satoru Shinriki DDSPhD Diagnostic Unit for Amyloidosis, Department of Laboratory Medicine, Kumamoto University Hospital, Kumamoto, JapanSearch for more papers by this authorMitsuharu Ueda MD, PhD, Mitsuharu Ueda MD, PhD Diagnostic Unit for Amyloidosis, Department of Laboratory Medicine, Kumamoto University Hospital, Kumamoto, JapanSearch for more papers by this authorTaro Yamashita MD, PhD, Taro Yamashita MD, PhD Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, JapanSearch for more papers by this authorShinichi Hirotani MD, PhD, Shinichi Hirotani MD, PhD Cardiovascular Division and Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, JapanSearch for more papers by this authorYukio Ando MD, PhD, Yukio Ando MD, PhD Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, JapanSearch for more papers by this author Konen Obayashi MD, PhD, Konen Obayashi MD, PhD Diagnostic Unit for Amyloidosis, Department of Laboratory Medicine, Kumamoto University Hospital, Kumamoto, JapanSearch for more papers by this authorYohei Misumi MD, PhD, Yohei Misumi MD, PhD Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, JapanSearch for more papers by this authorTetsuya Watanabe MD, Tetsuya Watanabe MD Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, JapanSearch for more papers by this authorTomotaka Ando MD, Tomotaka Ando MD Cardiovascular Division and Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, JapanSearch for more papers by this authorTakafumi Akagami MD, PhD, Takafumi Akagami MD, PhD Division of Coronary Heart Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, JapanSearch for more papers by this authorMasayoshi Tasaki MPAS, Masayoshi Tasaki MPAS Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, JapanSearch for more papers by this authorSatoru Shinriki DDSPhD, Satoru Shinriki DDSPhD Diagnostic Unit for Amyloidosis, Department of Laboratory Medicine, Kumamoto University Hospital, Kumamoto, JapanSearch for more papers by this authorMitsuharu Ueda MD, PhD, Mitsuharu Ueda MD, PhD Diagnostic Unit for Amyloidosis, Department of Laboratory Medicine, Kumamoto University Hospital, Kumamoto, JapanSearch for more papers by this authorTaro Yamashita MD, PhD, Taro Yamashita MD, PhD Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, JapanSearch for more papers by this authorShinichi Hirotani MD, PhD, Shinichi Hirotani MD, PhD Cardiovascular Division and Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, JapanSearch for more papers by this authorYukio Ando MD, PhD, Yukio Ando MD, PhD Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, JapanSearch for more papers by this author First published: 08 July 2013 https://doi.org/10.1002/mus.23939Citations: 2Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article.Citing Literature Volume48, Issue5November 2013Pages 839-841 RelatedInformation

Genotype – phenotype correlation in FAP

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.

Familial amyloidotic polyneuropathy type IV – gelsolin 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.

Regional differences and similarities of familial amyloidotic polyneuropathy (FAP) presentation in Brazil

Familial amyloidotic polyneuropathy (FAP) is a worldwide disease with various clinical presentations according to geographical origin of the cases. Brazil is a country of Portuguese colonization and Portuguese descendants are estimated to be more than 25 millions. The Brazilian FAP population was characterized in this text as having basically the same diseases characteristics as the most common Portuguese FAP type I patients.

Clinical and histopathological features of familial amyloidotic polyneuropathy with transthyretin Val30Ala in a Chinese family

Familial amyloidotic polyneuropathy (FAP) is characterized by extracellular deposition of amyloid fibrils caused by a point mutation in the transthyretin ( TTR) gene. TTR amyloidosis is linked to a vast number of mutations with varying phenotype and tissue distribution. Several Chinese kindred with FAP type 1 have been reported in Beijing, Hong Kong, Taiwan, and elsewhere. Here, histopathological features and TTR gene polymorphism were analyzed by using autopsy and blood specimens from a Chinese proband of a family with FAP. This proband is a 34-year old man with FAP type 1 who developed motor, sensory and autonomic impairments with neuropathy, gastrointestinal dysfunction, and orthostatic hypotension. Genetic findings of TTR revealed a T to C transition in codon 30 causing the mutation TTR Ala30. This patient died of respiratory and circulatory failure 7 years after onset. Autopsy showed heavy amyloid deposition in the peripheral nerves, liver, testes, thyroid, pancreas and muscles. There was moderate deposition in the heart, kidneys, bladder, gastrointestinal tract, tongue, lung, blood vessels, and gall bladder. The spleen showed only slight deposition, and none was observed in the central nervous system. TTR amyloidosis was confirmed by immunochemical staining with a specific TTR antibody. These results indicate that the distribution of amyloid deposition, (i.e., heavy in the liver, testes and slight in the spleen), is a characteristic feature and reflects the severity of FAP with TTR Val30Ala.

Heart Failure and Cardiac Involvement as Isolated Manifestation of Familial Form of Transthyretin Amyloidosis Resulting From Val30Met Mutation With No Clinical Signs of Polyneuropathy

A 63-year-old white man with a 6-month history of progressive exertional dyspnea was referred for evaluation. In 1997, he presented an episode of unconsciousness as first symptom of a cardiac disease. In 2003, arterial hypertension, as well as atrioventricular block Mobitz type I, was diagnosed. A worsening of the biventricular heart failure over the last 2 years led to his admission at our clinic in 2008, with dyspnea at rest and bilateral pleural effusions. At admission, the patient appeared to be well, with a blood pressure of 142/76 mm Hg and a pulse of 97 bpm. Jugular venous pulse was not elevated, but mild bilateral edema of the lower extremities was noted. The lungs were clear to auscultation, with attenuation on the right side because of pleural effusion. The patient’s symptoms improved slightly through pharmacological therapy, but he remained in New York Heart Association functional class III heart failure. Laboratory studies revealed normal blood cell counts and electrolyte panel, with signs of load on the right side of the heart. The highest B-type natriuretic peptide was 818.6 pg/mL (normal, <100 pg/mL). The 24-hour urine protein collection was outside of normal limits at 0.27 g (normal, <0.15 g), and glomerular filtration rate according to the modified …

Clinical and histopathological features of progressive-type familial amyloidotic polyneuropathy with TTR Lys54

The purpose of this study was to evaluate the clinical and pathological features in patients with progressive-type familial amyloidotic polyneuropathy (FAP) using autopsy and biopsy specimens. A proband is a 33-year-old man with FAP type I who developed motor, sensory and autonomic impairments with neuropathy, heart failure, and anorexia. Genetic findings of transthyretin (TTR) revealed G to A transition in codon 54 causing a rare mutation of TTR Lys54. He died of pneumonia and severe cardiac failure 4 years after onset. Autopsy showed heavy amyloid deposition in the heart, peripheral nerves, thyroid, skin, fat tissue, prostate and testis, moderate in the sympathetic nerve trunk, vagal nerve, celiac plexus, pelvic plexus, bladder, gastrointestinal tract, tongue, pancreas, lung, pituitary, blood vessel, gall bladder, adrenals and muscles, and free in the central nervous system, liver, kidney and spleen. Sural nerve biopsy in a sibling confirmed TTR amyloidosis immunohistochemically. Electronmicroscopic findings of amyloid fibrils were similar to that of FAP Met30. Immunoelectronmicroscopic findings indicated the relationship between amyloid fibrils or non-fibrillar structure and collagen fibers. The distribution of amyloid deposition, heavy in the heart and lacking in the kidney, is a characteristic feature and reflected severity of FAP with TTR Lys54.

Clinical variability in type I familial amyloid polyneuropathy (Val30Met): Comparison between late‐ and early‐onset cases in Portugal

We compared early- with late-onset cases in 86 patients with familial amyloidotic polyneuropathy type I (FAP). Among these patients, 43 presented before age 50 (early-onset) and 43 after this age (late-onset). Sex and geographical distribution were similar, although a family history of the disorder was more frequent in early-onset cases. In late-onset disease, autonomic dysfunction was less frequent, but organ involvement and severe neuropathic pain were more frequent. Neurophysiological measurements were similar. FAP is a cause of neuropathy in elderly patients, in particular in those presenting with neuropathic pain.

Exercise testing for assessment of autonomic dysfunction in patients with familial amyloidotic polyneuropathy type I

Exercise testing for assessment of autonomic dysfunction in patients with familial amyloidotic polyneuropathy type I

Aging and transthyretin-related amyloidosis: Pathologic examinations in pulmonary amyloidosis

Although aging is closely related with the onset of senile systemic amyloidosis (SSA) caused by wild-type transthyretin (TTR), the effect of aging on amyloid formation has remained unclear in familial amyloidotic polyneuropathy (FAP), caused by variant- and wild-type TTR. The aim of this study was to elucidate the effects of aging and/or other factors in FAP on amyloid formation in the lung, one of the most important target organs of amyloid deposition in SSA. Pulmonary amyloid distribution was determined using 19 autopsied lung samples from patients with FAP amyloidogenic TTR (ATTR) V30M, the most common type of FAP. Amyloid deposition was observed around the walls of the bronchi/ bronchioles, the pulmonary arteries, and the pulmonary veins, while no amyloid deposits could be found around the lymphatics. In addition, amyloid deposition in the alveolar regions was a characteristic finding in aged patients with FAP ATTR V30M (average ages of the patients with amyloid positive vs. negative: 50.55 ± 8.75 vs. 39.75 ± 4.17 years old, p < 0.005), similar to the finding in one SSA patient. These results suggest that aging could play an important role in the progression of pulmonary amyloid formation in FAP ATTR V30M.

Polineuropatía amiloidótica familiar tipo I: Report of one case

Familial amyloidotic polyneuropathy type I is an autosomal dominant inherited disorder characterized by progressive peripheral and autonomic neuropathy, associated with neural and systemic amyloid deposits. The abnormality usually lies in the transthyretin (TTR) gene. We report a 25 years old man with 18 months history of dysesthesias and pain in the toes, abnormal micturition and sexual dysfunction. Neurophysiologically studies disclosed a sensory-motor axonal polyneuropathy. Autonomic tests showed sympathetic and parasympathetic involvement. An electron micrograph of sural nerve revealed amyloid fibrils in the endoneurium. His mother died after a clinical history suggestive, in retrospect, of familial amyloidotic polyneuropathy type I. The clinical and genetic analysis of this cause of polyneuropathy are discussed.

Genetics of familial amyloidotic polyneuropathy in a Hong Kong Chinese kindred.

Familial amyloidotic polyneuropathy type 1 (FAP1, MIM176300) is an autosomal dominant disease caused by mutations in the transthyretin (TTR) gene. An extended Chinese kindred of FAP1 was first reported in Hong Kong in 1989, three of the four histologically proven subjects have deceased. TTR gene mutations were not studied then. A DNA-based diagnosis was performed on FAP1 by restriction analysis and direct DNA sequencing was carried out on a symptomatic member of this family who had undergone a liver transplantation. It showed a substitution of thymine by cytosine in the second base of codon 30 in exon 2 of the TTR gene, with the creation of a novel HhaI restriction endonuclease site. Valine is substituted by alanine (V30A) in the mutant TTR. Both restriction analysis and direct sequencing revealed the same mutation in one of the two asymptomatic siblings. This mutation was first reported in a FAP1 family of German descent.