Postmortem findings in a familial amyloid polyneuropathy patient with homozygosity of the mutant Val30Met transthyretin gene

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.     

Diagnosis of sporadic transthyretin Val30Met familial amyloid polyneuropathy: a practical analysis

Transthyretin (TTR) Val30Met-associated familial amyloid polyneuropathy (FAP ATTR Val30Met) is the most common form of FAP and is now prevalent in areas other than those seen within conventional endemic foci. We investigated 15 patients with FAP ATTR Val30Met without a family history of FAP who were referred for sural nerve biopsy. Initial symptoms included somatic neuropathy in all patients, while sensory dissociation and autonomic symptoms were apparent only in two and seven patients, respectively. Nonspecific neuropathic features and slight abnormalities in cerebrospinal fluid protein levels and in electrophysiological indices related to nerve conduction led clinicians to initially suspect chronic inflammatory demyelinating polyneuropathy (CIDP) in some patients. Small-fiber predominant loss was observed in a minority of patients. In terms of cardiac involvement, findings suggestive of subclinical cardiomyopathy due to amyloid deposition, such as cardiomegaly on chest X-ray, thickening of the interventricular septum, and granular sparkling echo on echocardiography, were seen alone or in combination in 11 of 14 examined patients. In conclusion, clinicians should consider the possibility of FAP ATTR Val30Met in patients presenting with neuropathy of undetermined etiology to avoid misdiagnosis. Detecting subclinical cardiac involvement may help to diagnose late-onset FAP ATTR Val30Met in those without a family history of the disease.     

The significance of carpal tunnel syndrome in transthyretin Val30Met familial amyloid polyneuropathy

Carpal tunnel syndrome (CTS) is frequently reported in association with amyloidosis. We determined the significance of CTS in transthyretin Val30Met-associated familial amyloid polyneuropathy (FAP ATTR Val30Met) by comparing the electrophysiological indices of the median and ulnar nerves in 58 patients. As a whole, sensory nerve conduction velocity (SCV) was slowed and distal motor latency (DML) was prolonged to a similar extent in the median and ulnar nerves in these patients. The extent of abnormalities in the median nerve was almost similar to that in the ulnar nerve in both early-onset cases from endemic foci and late-onset cases from non-endemic areas. In age-matched idiopathic patients with CTS (20 patients, 27 hands), the slowing of SCV and the prolongation of DML in the median nerve were significant, while the slowing of motor conduction velocity was much less compared to FAP ATTR Val30Met patients. Although concomitant lesions in the ulnar nerve entrapment site at the wrist cannot be excluded, these findings indicate that CTS is not the sole distinctive feature in the majority of FAP ATTR Val30Met patients. The electrophysiological abnormality at the distal portion of the median nerve may be a consequence of polyneuropathy rather than an entrapment injury.     

Spinal cord stimulation markedly ameliorated refractory neuropathic pain in transthyretin Val30Met familial amyloid polyneuropathy

Although spinal cord stimulation has been reported to be effective for controlling neuropathic pain in diabetic neuropathy, it has rarely been investigated in other peripheral neuropathies. We describe, for the first time, the efficacy of spinal cord stimulation for refractory neuropathic pain in a patient with transthyretin Val30Met associated familial amyloid polyneuropathy (FAP ATTR Val30Met). A 72-year-old man was diagnosed as having FAP ATTR Val30Met when he was 70 years old. He had been complained of burning pain in the distal portion of his bilateral lower limbs since he was 69 years old. Because conventional symptomatic therapies, including nonsteroidal anti-inflammatory drugs, antiepileptic drugs, and tricyclic antidepressants did not ameliorate pain, he underwent bilateral lumbar spinal cord electrical stimulation at high frequency and low voltage at the level of Th12 vertebral body and this was markedly effective. Our case expands the application of spinal cord stimulation, which should be considered as an alternative therapeutic approach for relief of neuropathic pain, which can be extremely distressful for patients and may lead to an impaired quality of life.     

Analysis of transthyretin amyloid fibrils from vitreous samples in familial amyloidotic polyneuropathy (Val30Met).

The aim of the present study was to analyze the forms of wild type and mutated monomeric transthyretin (Val30Met) in the amyloid fibrils of patients with familial amyloidotic polyneuropathy by electrospray ionization mass spectrometry (ESI-MS). The solubility of amyloid fibrils from the vitrectomized samples was examined to determine the appropriate solution for ESI-MS. ESI-MS analysis revealed that heterozygotic Val30Met amyloid fibrils contained 14.6 +/- 7.5% normal TTR. In all samples, 3 different types of variant ATTR could be identified: Full length ATTR, and -57, and -157 (or 156) Da from ATTR Val30Met were found. The two peaks showing -57, and -157 (or 156) Da from ATTR Val30Met corresponded to the -Gly, and -Gly-Pro sequences of ATTR Val30Met from the N-terminal. The results illustrate the heterogeneity of ATTR amyloid deposits and this method may be very useful for analyzing amyloid fibrils in ATTR related amyloidosis.     

Heterogeneity of penetrance in familial amyloid polyneuropathy,ATTR Val30Met,in the Swedish population

Transthyretin (TTR) familial amyloid polyneuropathies (FAP) are autosomal dominant devastating afflictions. They were first described in Portugal, later in Japan and Sweden and are now recognized worldwide. The TTR Val30Met mutation is the most common, and depending on the geographic origin, a wide variation in age at onset of the disease is observed. In Europe, northern Sweden is the second most prevalent area of the disease, and a late age of onset of 56 years has been reported. The present study aims to estimate the penetrance in TTR Val30Met Swedish families. Genealogical investigations, clinical data and genotyping were obtained in 77 TTR-Val30Met Swedish families. The penetrance in Val30Met carriers and variation within the endemic area, according to gender and transmitting parents were calculated by a newly developed bias-free method. The penetrance estimates were low, i.e. 1.7% and 22% at age 30 and 60 years, respectively, and far from complete (69%) by age 90 years. Differences between Piteå and Skellefteå regions were observed. Moreover, penetrance was significantly higher when the mutation was inherited from the mother than from the father. The low penetrance observed in TTR FAP kindreds and its variations is important information for the genetic counseling and treatment of Swedish FAP patients and their families.     

Familial amyloidotic polyneuropathy type 1 in Brazil is associated with the transthyretin Val30Met variant.

Familial amyloidotic polyneuropathy type 1 (FAP1) is an inherited systemic amyloidosis that is secondary to the deposition of transthyretin (TTR) variants in peripheral nerves and in certain visceral organs. More than 50 distinct mutations have already been described in the TTR gene. Yet, the most common mutation found worldwide is a substitution of valine for methionine in position 30 (Val30Met). Currently, the variants of TTR in Brazilian FAP1 patients remain largely unknown and the aim of this study was to analyze the frequency of the TTR Val30Met mutation in such Brazilian subjects. METHODS: Thirty-two FAP1 patients belonging to 24 different families were studied for the presence of Val30Met variant by PCR-RFLP. RESULTS: All Brazilian FAP1 subjects studied were positive for the TTR Val30Met variant. As expected, all of them were heterozygous for the mutation. CONCLUSION: TTR Val30Met mutation was the sole TTR variant found in Brazilian FAP1 patients in this cohort, and it was present even in those subjects without a clear history of Portuguese ancestry.     

Value of renal biopsy in the prognosis of liver transplantation in familial amyloid polyneuropathy ATTR Val30Met patients.

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.     

Serum transthyretin monomer in patients with familial amyloid polyneuropathy.

Although dissociation of the transthyretin (TTR) tetramer is suspected of being the first step in amyloid fibril formation in hereditary TTR amyloidosis, including familial amyloid polyneuropathy (FAP), the TTR monomer has never been examined in vivo. Therefore, we analyzed the TTR monomer in the serum of FAP patients and normal individuals. Free TTR monomer was detected in both groups using gel filtration chromatography and immunoblotting. Both the mean concentration of free TTR monomer and the total serum TTR were significantly lower in FAP patients than in normal individuals. Moreover, in FAP patients, mass spectrometry showed that the variant TTR monomer was markedly decreased compared with the wild-type TTR monomer. These findings suggest that the free variant TTR monomer is unstable in serum, and that it aggregates in deposits in various organs or is adsorbed by preexisting amyloid fibrils before it is degraded     

Value of renal biopsy in the prognosis of liver transplantation in familial amyloid polyneuropathy ATTR Val30Met patients

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.     

Vitreous amyloidosis after liver transplantation in patients with familial amyloid polyneuropathy: ocular synthesis of mutant transthyretin.

Vitreous amyloidosis has been reported in patients with familial amyloidotic polyneuropathy (FAP) who are carriers of different mutant transthyretins (TTR). The mutant TTR constitutes the majority of the amyloid vitreous fibrils in heterozygous Val30Met patients. Due to the ocular synthesis of TTR, it is possible that the retina constitutes the source of vitreous amyloid fibrils, if so, orthotopic liver transplantation (OLT) performed to remove the mutant TTR from circulation might not be effective in treating/avoiding vitreous amyloid. We present vitreous amyloidosis in a FAP patient from Maiorca with ATTR Val30Met who underwent OLT at age 38. Progressive impairment of visual acuity (VA) appeared bilaterally 2 years after OLT due to vitreous opacities consistent with amyloid; successful bilateral vitrectomy was performed. Amyloid was demonstrated in the vitrectomy material by Congo red staining, immunohistochemistry and Western blotting analyses were positive with an antibody for human TTR. Mass spectrometry of TTR revealed the presence of the mutant in approximately 20% of the TTR. Future structural studies on vitreous material with different proportions of normal/versus mutant TTR might shed some light on TTR fibrillogenesis. These results show that vitreous deposition of TTR amyloidfibrils occurs after OLT, suggesting that ongoing intraocular synthesis of mutant TTR might contribute to this process. We also present the progression after OLT of vitreous amyloidosis previously diagnosed in three patients with TTR Val71Ala.     

Noninvasive cardiovascular findings in familial amyloid polyneuropathy.

The cardiovascular system was examined in 19 cases of familial amyloid polyneuropathy. In a group of patients with neurological involvement, various cardiac abnormalities were common, including orthostatic hypotension, prominent apex cardiographic A waves, abnormal apical systolic waves (bulges), systolic murmurs, mid-systolic clicks, QS waves, atrioventricular block, left bundlebranch block, and abnormalities of ejection time and pre-ejection period. Though there was one case with pronounced cardiac abnormality despite a normal neurological state, and though cardiovascular symptoms appeared later than neurological symptoms, the degree of cardiac involvement generally paralleled the severity of the neurological disorder.     

Japanese monozygotic twins with familial amyloidotic polyneuropathy (FAP) (ATTR Val30Met).

Twenty-nine-year-old twin brothers having the amyloidogenic transthyretin (ATTR) Val30Met gene developed the clinical symptoms of familial amyloidotic polyneuropathy (FAP) in 1995. The twins had the same educational background and lived in the same district. FAP manifestations were similar in both cases, although electromyographic examinations revealed sensorimotor polyneuropathy in No. 1 and sensory polyneuropathy in No. 2. DNA analysis revealed that they were monozygotic twins. In addition to environmental factors, genetic factors may play an important role in determining the onset of FAP.     

Successful pregnancies and fatherhood in familial amyloidotic polyneuropathy (FAP Val30Met) patients with liver transplantation.

For familial amyloidotic polyneuropathy (FAP) patients, several problems regarding reproduction are present. For males, erectile dysfunction and retrograde ejaculation are well known complications of the disease In addition, the risk of transferring a fatal disease to their offspring is a matter of concern for the patients. For transplanted fertile patients, the risk of side effects of immunosupression therapy causing congenital malformations must be addressed, and for female patients the additional risk of complications during pregnancy and delivery is a case of concern. After delivery, the problem of breast-feeding arises. In the Swedish population of transplanted patients, five successful pregnancies, of which male FAP recipients fathered three, are reported. All patients were on stable immunosuppressive therapy with cyclosporine or tacrolimus and prednisolone. From our experience, successful fatherhood and pregnancy is possible for liver transplanted FAP patients, as it has been reported for patients transplanted for other medical reasons.     

Trigger finger as an initial manifestation of familial amyloid polyneuropathy in a patient with Ile107Val TTR

We describe a Japanese family with transthyretin Val107-related familial amyloid polyneuropathy (FAP). The clinical features were high-aged onset, sensorimotor polyneuropathy, carpal tunnel syndrome (CTS) and trigger finger. In addition, the proband showed cardiac conduction block and amyloid deposition in the sural nerve and dermis. Trigger finger may be a so far unknown clinical manifestation of Val107 FAP due to amyloid deposition in the connective tissue like CTS.     

Successful pregnancies and fatherhood in familial amyloidotic polyneuropathy (FAP Val30Met) patients with liver transplantation

For familial amyloidotic polyneuropathy (FAP) patients, several problems regarding reproduction are present. For males, erectile dysfunction and retrograde ejaculation are well known complications of the disease In addition, the risk of transferring a fatal disease to their offspring is a matter of concern for the patients. For transplanted fertile patients, the risk of side effects of immunosupression therapy causing congenital malformations must be addressed, and for female patients the additional risk of complications during pregnancy and delivery is a case of concern. After delivery, the problem of breast-feeding arises. In the Swedish population of transplanted patients, five successful pregnancies, of which male FAP recipients fathered three, are reported. All patients were on stable immunosuppressive therapy with cyclosporine or tacrolimus and prednisolone. From our experience, successful fatherhood and pregnancy is possible for liver transplanted FAP patients, as it has been reported for patients transplanted for other medical reasons.     

Gastrointestinal dysfunction in familial amyloidotic polyneuropathy (ATTR Val30Met)--comparison of Swedish and Japanese patients.

The aim of the present study was to compare the clinical symptoms of Swedish and Japanese patients with familial amyloidotic polyneuropathy (ATTR Val30Met), especially gastrointestinal disturbances, and to correlate the findings with survival. Seventy-three Swedish and 47 Japanese patients were available for the study. Thirty-two Swedish and 7 Japanese patients had undergone liver transplantation. The mean age at onset was 50 for Swedish and 35 for Japanese patients (P < 0.001; non-transplanted patients). Fifty-five percent of Japanese patients had gastrointestinal disturbances from onset, compared to 22% of Swedish patients (P < 0.05; whole population). The Swedish patients average survival after the onset was significantly longer than Japanese patients (P < 0.05; non-transplanted patients). An early onset of gastrointestinal symptoms was correlated to a decreased survival for Swedish, but not for Japanese patients. Age at onset was not correlated to survival neither for Swedish nor for Japanese patients. We conclude that the clinical expressions of familial amyloidotic polyneuropathy ATTR Val30Met are different in Swedish and Japanese patients. The survival after the onset was shorter for Japanese patients, who also had an earlier onset of gastrointestinal disturbances, especially diarrhea than Swedish patients.     

Frequency of the transthyretin Val30Met mutation in the northern Swedish population

Abstract

By genotyping a large number of samples from the Northern Sweden Health and Disease Study cohort, a carrier frequency could be determined for the Skellefteå and Lycksele populations. A previous study of the amyloidogenic transthyretin mutation TTRV30M in Northern Sweden’s endemic area has shown a large variation in carrier frequency and penetrance of the trait within the area. However, the estimations have been based on a small sample size within the different regions in the area and therefore, the wide variation in TTRV30M carrier frequency observed between the Lycksele and Skellefteå populations are uncertain. Based on a total of 3460 samples, the estimated overall carrier frequency in the two regions was 1.82% with a carrier frequency in the Skellefteå and Lycksele population of 1.63% and 2.02%, respectively. Thus, the previously reported extremely high frequency in the Lycksele region compared to that of the Skellefteå region could not be substantiated. However, it does not change the previous finding of a surprisingly higher carrier frequency in the population from endemic area of Northern Sweden compared to that reported from endemic areas in Portugal.     

Transthyretin Met 30 familial amyloid polyneuropathy in China. Usefulness of mass spectrometry for screening a variant TTR in serum

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