| 1. |
- Heldestad, Victoria, 1970-, et al.
(author)
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Comparison of quantitative sensory testing and heart rate variability in Swedish Val30Met ATTR
- 2011
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In: Amyloid. - Pearl River, NY : Parthenon Pub.. - 1350-6129 .- 1744-2818. ; 18:4, s. 183-190
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Journal article (peer-reviewed)abstract
- Patients with transthyretin amyloidosis (ATTR) polyneuropathy, a hereditary fatal disease, often report defects in both thermal perception and autonomic nervous system function as their first clinical symptoms. While elevated thermal perception thresholds (TPT) for cold and warmth only recently have been shown as an early marker of small nerve fiber dysfunction in these patients, heart rate variability (HRV) has frequently been used to quantify autonomic neuropathy. The main purpose with this report was to elucidate a possible relationship between estimates of HRV and TPT in a selected group of early and late-onset Swedish Val30Met ATTR patients. The results show significantly more pronounced elevation of TPT in early compared to late-onset patients. Significant correlations between HRV and TPT were found among late-onset cases, indicating a possible relationship between loss of thin nerve fibers in somatic and autonomic nerves, while generally no such relationships were found among early-onset cases. This observation emphasizes the importance of testing both HRV and TPT to ensure optimal early detection of neuropathic changes in an as wide as possible range of small nerve fibers in suspected ATTR patients. This is of particular importance as the phenotype of the ATTR disease varies between groups with different age of onset.
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| 2. |
- Obayashi, Konen, et al.
(author)
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Blood pressure overshoot after tilt reversal in patients with familial amyloidotic polyneuropathy
- 2011
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In: Hypertension Research. - : Springer Science and Business Media LLC. - 0916-9636 .- 1348-4214. ; 34:1, s. 133-138
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Journal article (peer-reviewed)abstract
- The pathophysiology of the hemodynamic responses to postural stress in familial amyloidotic polyneuropathy (FAP) remains to be elucidated. The aim of the study was to evaluate hemodynamic responses after tilt reversal in FAP. Systolic blood pressure (BP) and heart rate variability (HRV) were analyzed in the baseline, 70° upright position, and after tilt reversal in 15 FAP patients and 14 healthy controls. Beat-to-beat BP was recorded with a Finapres device. Maximum systolic BP after tilt reversal was increased with 22±13 mm Hg in FAP patients as compared with baseline (BP overshoot), whereas controls showed a significantly lower BP overshoot (8±6 mm Hg, P<0.001). In all states, total spectral power and the power of the low and high frequency components were all significantly lower than those of the controls (P<0.01). In a linear regression analysis adjusted for age, we found a significant inverse relation between BP overshoot and HRV (total spectral power, power of the low-frequency and high-frequency components) in all three states (standardized β between -0.74 to -0.53, P<0.01). Five FAP patients presented a trial arrhythmia precluding HRV analysis: four of those presented BP overshoots 12 mm Hg. BP overshoot may be a marker to assess the progression of cardiac autonomic dysfunction, especially as heart arrhythmia in many FAP patients prevent HRV analysis. In addition, assessment of the post-tilt BP reaction points to possible treatment modalities for orthostatic hypotension at least in the early stages of the disease.
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| 3. |
- Obayashi, Konen, et al.
(author)
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Impact of antibodies against amyloidogenic transthyretin (ATTR) on phenotypes of patients with familial amyloidotic polyneuropathy (FAP) ATTR Valine30Methionine
- 2013
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In: Clinica Chimica Acta. - : Elsevier BV. - 0009-8981 .- 1873-3492. ; 419C, s. 127-131
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Journal article (peer-reviewed)abstract
- BACKGROUND: This study investigated whether a relationship exists between the presence of de novo antibodies and the clinical manifestations of familial amyloidotic polyneuropathy (FAP). METHODS: Serum samples were collected from 25 Japanese and 6 Swedish FAP amyloidogenic transthyretin (ATTR) Valine30Methionine (V30M) patients, 4 asymptomatic Japanese ATTR V30M gene carriers, and 24 Japanese healthy volunteers. Study methods included enzyme-linked immunosorbent assay (ELISA) and mass spectrometry. RESULTS: Three Japanese and 5 Swedish patients had significantly higher levels of antibodies against ATTR than did healthy volunteers and asymptomatic gene carriers (P<0.05). All 8 patients with higher antibody levels were late-onset cases. The ratio of wild-type TTR to ATTR V30M in serum from the high-antibody group was higher than that of the low-antibody group. ELISA results revealed two epitopes at positions 24-35 and 105-115 of ATTR V30M. We found a significant positive correlation between levels of the antibody at positions 24-35 and the age at FAP onset (r=0.751, P<0.05). An age-dependent increase in the occurrence of antibodies was observed in these patients with an epitope at positions 24-35. CONCLUSIONS: These findings may help explain the differences in early- and late-onset FAP and/or the progression of FAP.
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| 4. |
- Obayashi, Konen, et al.
(author)
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Impact of serotonin transporter and catechol-O-methyl transferase genes polymorphism on gastrointestinal dysfunction in Swedish and Japanese familial amyloidotic polyneuropathy patients.
- 2008
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In: Clinica Chimica Acta. - : Elsevier BV. - 0009-8981 .- 1873-3492. ; 398:1-2, s. 10-4
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Journal article (peer-reviewed)abstract
- BACKGROUND: Differences in the gastrointestinal manifestations have emerged between Swedish and Japanese familial amyloidotic polyneuropathy amyloidogenic transthyretin Valine30Methionine (FAP ATTR Val30Met) patients. To elucidate the cause of the differences, we investigated the associations between serotonin transporter gene-linked polymorphic region (5-HTTLPR) and/or catechol-O-methyl transferase (COMT) gene polymorphism and their gastrointestinal in these patients. METHODS: Twenty-six Swedish and 24 Japanese patients with gastrointestinal disturbances, in whom genetic material was available, were included in the study. The initial gastrointestinal manifestations of the disease were classified as constipation, constipation alternating with diarrhoea, continuous diarrhoea, and nausea/vomiting. 5-HTTLPR and COMT gene polymorphism were assessed by polymerase chain reaction and enzymatic digestion. RESULTS: A significantly higher LA allele frequency of 5-HTTLPR was noted in the Swedish population compared with that of the Japanese. Moreover, the LA allele frequency tended to be lower in the continuous diarrhoea group than in that of the remaining groups of both Swedish and Japanese patients. No association between COMT genotype and initial gastrointestinal symptoms was noted. CONCLUSION: A high expression of serotonin transporter induced by LA allele of 5-HTTLPR may be one of the factors implicated with the inhibition of severe diarrhoea in early stages of Swedish FAP ATTR Val30Met patients.
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| 5. |
- Okamoto, Sadahisa, et al.
(author)
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Continuous development of arrhythmia is observed in Swedish transplant patients with familial amyloidotic polyneuropathy (amyloidogenic transthyretin Val30Met variant)
- 2011
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In: Liver transplantation. - : Ovid Technologies (Wolters Kluwer Health). - 1527-6465 .- 1527-6473. ; 17:2, s. 122-128
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Journal article (peer-reviewed)abstract
- In patients with familial amyloidotic polyneuropathy (FAP), heart complications are prognostic factors for mortality and morbidity after liver transplantation (LT). However, only a few studies have analyzed the development of arrhythmia in transplant patients with FAP. We investigated the development of arrhythmia requiring pacemaker insertion (PMI) in Swedish transplant patients with FAP, and we related the findings to gender, age at disease onset, and survival. One hundred four transplant patients with the amyloidogenic transthyretin Val30Met mutation were included in the study. Twenty-six (25%) received a pacemaker during the observation period (a median of 11 years after disease onset). This frequency was comparable to that noted in a previous study describing the natural course of FAP. No significant differences in PMI between early-onset cases (<50 years old) and late-onset cases (≥ 50 years old) or between genders were observed. PMI was not significantly related to patient survival. Our study confirms our previously reported short-time observation: LT does not prevent the development of heart arrhythmia necessitating PMI. The development of arrhythmia is unrelated to gender or age at disease onset, and the yearly risk does not appear to decrease with time after LT.
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| 6. |
- Okamoto, Sadahisa, et al.
(author)
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Liver transplantation for familial amyloidotic polyneuropathy : impact on Swedish patients' survival
- 2009
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In: Liver transplantation. - : John Wiley & Sons. - 1527-6465 .- 1527-6473. ; 15:10, s. 1229-1235
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Journal article (peer-reviewed)abstract
- Liver transplantation (LTx) for familial amyloidotic polyneuropathy (FAP) is an accepted treatment for this fatal disease. However, the long-term outcome with respect to that of nontransplanted patients has not been fully elucidated. The aim of this study was to compare the long-term survival of Swedish LTx FAP patients with that of historical controls, especially with respect to the age at onset of the disease and gender. In order to evaluate the outcome of LTx as a treatment for FAP, survival was calculated from the onset of disease. One hundred forty-one FAP patients, 108 transplanted and 33 not transplanted, were included in the study. Significantly increased survival was noted for LTx patients in comparison with controls. The outcome was especially favorable for those with an early onset of the disease (age at onset < 50 years) in comparison with early-onset controls (P < 0.001). In contrast, no significant difference for late-onset cases (> or = 50 years) was found. Transplanted late-onset females had significantly improved survival in comparison with transplanted late-onset males (P = 0.02). We were unable to find significant differences in survival between patients with long (> or = 7 years) or short (<7 years) disease duration at transplantation. The survival of male patients with late-onset disease appeared not to improve with LTx. LTx is an efficacious treatment for improving the survival of early-onset FAP patients. Further studies are needed to analyze the cause of the poorer outcome for late-onset male patients.
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| 7. |
- Olsson, Malin, et al.
(author)
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A possible role for miRNA silencing in disease phenotype variation in Swedish transthyretin V30M carriers
- 2010
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In: BMC Medical Genetics. - : Springer Science and Business Media LLC. - 1471-2350. ; 11, s. 130-
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Journal article (peer-reviewed)abstract
- Our results are the first to show the presence of a 3'UTR polymorphism on the V30M haplotype in Swedish carriers, which can serve as a miRNA binding site potentially leading to down-regulated expression from the mutated TTR allele. This finding may be related to the low penetrance and high age at onset of the disease observed in the Swedish patient population.
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| 8. |
- Oshima, Toshinori, et al.
(author)
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Changes in pathological and biochemical findings of systemic tissue sites in familial amyloid polyneuropathy more than 10 years after liver transplantation
- 2014
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In: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ. - 0022-3050 .- 1468-330X. ; 85:7, s. 740-746
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Journal article (peer-reviewed)abstract
- Objective To elucidate the long-term effects of liver transplantation (LT) on familial amyloid polyneuropathy (FAP). Methods We investigated clinicopathological and biochemical characteristics of systemic tissues in four autopsied cases of FAP patients surviving more than 10 years after LT and seven autopsied cases without LT. For analysing the truncated form of transthyretin (TTR) in amyloid, we also employed specimens from additional 18 FAP patients. Results Several tissue sites such as the heart, tongue and spinal cord had moderate-to-severe amyloid deposits but other tissues showed no or mild amyloid deposition. Those findings seemed similar to those observed in senile systemic amyloidosis (SSA), a sporadic amyloidosis caused by wild-type (WT) TTR. Also, amyloid deposits in systemic tissue sites except for the spinal cord in patients after LT derived mostly from WT TTR secreted from the normal liver grafts. In addition, in non-transplantation patients, proportions of WT TTR seemed to be relatively high in those tissue sites in which patients after LT had severe amyloid deposition, which suggests that WT TTR tends to form amyloid in those tissue sites. Finally, although the truncation of TTR in amyloid deposits did not depend on undergoing LT, we elucidated the truncation of TTR occurred predominantly in patients from non-endemic areas of Japan, where FAP amyloidogenic TTR V30M patients are late onset and low penetrance, compared with patients from an endemic area of Japan. Conclusions FAP may shift to systemic WT TTR amyloid formation after LT, which seems to be similar to the process in SSA. The truncation of TTR in amyloid deposits may depend on some genetic or environmental factors other than undergoing LT.
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| 9. |
- Wixner, Jonas, et al.
(author)
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Loss of gastric interstitial cells of Cajal in patients with hereditary transthyretin amyloidosis
- 2013
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In: Amyloid. - : Informa Healthcare. - 1350-6129 .- 1744-2818. ; 20:2, s. 99-106
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Journal article (peer-reviewed)abstract
- Background: Hereditary transthyretin (TTR) amyloidosis is a systemic neuropathic disorder caused by TTR gene mutations. Gastrointestinal complications are common and the underlying mechanisms remain unclear. The interstitial cells of Cajal (ICC) function as pacemaker cells in the gastrointestinal tract and are important for gastrointestinal motility. The aim of this study was to investigate the densities of gastric ICC and nerves in patients with TTR amyloidosis compared to non-amyloidosis controls.Methods: Antral wall autopsy specimens from 11 Japanese ATTR V30M patients and 10 controls were analyzed with immunohistochemistry and computerized analysis. Antibodies to c-Kit and TMEM16A were used to assess ICC and an antibody to PGP 9.5 was used to assess nervous tissue. The study was approved by a Japanese ethical committee.Results: The densities of c-Kit-immunoreactive (IR) ICC were significantly lower in the circular and longitudinal muscle layers of patients compared to controls (p = 0.004 for both). Equivalent results were found for TMEM 16A-IR ICC. There were no significant differences in PGP 9.5-IR cells in the circular or longitudinal muscle layers between patients and controls (p = 0.173 and 0.099, respectively).Conclusions: A loss of gastrointestinal ICC may be an important factor for the digestive disturbances in hereditary TTR amyloidosis.
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| 10. |
- Yanagisawa, Akihiro, et al.
(author)
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Amyloid deposits derived from transthyretin in the ligamentum flavum as related to lumbar spinal canal stenosis.
- 2015
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In: Modern Pathology. - : Elsevier BV. - 0893-3952 .- 1530-0285. ; 28:2, s. 201-207
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Journal article (peer-reviewed)abstract
- Amyloidosis is a protein conformational disorder with the distinctive feature of extracellular accumulation of amyloid fibrils that come from different proteins. In the ligamentum flavum of the lumbar spine, amyloid deposits were frequently found in elderly patients with lumbar spinal canal stenosis and were at least partially formed by wild-type transthyretin. However, how amyloid deposits in the ligamentum flavum affect lumbar spinal canal stenosis has remained unclear. In this study, we analyzed clinical, pathologic, and radiologic findings of patients with lumbar spinal canal stenosis who had amyloid deposits in the ligamentum flavum. We studied 95 ligamentum flavum specimens obtained from 56 patients with lumbar spinal canal stenosis and 21 ligamentum flavum specimens obtained from 19 patients with lumbar disk herniation. We evaluated histopathologic findings and clinicoradiologic manifestations, such as thickness of the ligamentum flavum and lumbar spinal segmental instability. We found that all 95 ligamentum flavum specimens resected from patients with lumbar spinal canal stenosis had amyloid deposits, which we classified into two types, transthyretin-positive and transthyretin-negative, and that transthyretin amyloid formation in the ligamentum flavum of patients with lumbar spinal canal stenosis was an age-associated phenomenon. The amount of amyloid in the ligamentum flavum was related to clinical manifestations of lumbar spinal canal stenosis, such as thickness of the ligamentum flavum and lumbar spinal segmental instability, in the patients with lumbar spinal canal stenosis with transthyretin-positive amyloid deposits. To our knowledge, this report is the first to show clinicopathologic correlations in transthyretin amyloid deposits of the ligamentum flavum. In conclusion, transthyretin amyloid deposits in the ligamentum flavum may be related to the pathogenesis of lumbar spinal canal stenosis in elderly patients.Modern Pathology advance online publication, 5 September 2014; doi:10.1038/modpathol.2014.102.
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