A circulating, disease-specific, mechanism-linked biomarker for ATTR polyneuropathy diagnosis and response to therapy prediction.

The transthyretin (TTR) amyloidoses (ATTR) are progressive, degenerative diseases resulting from dissociation of the TTR tetramer to monomers, which subsequently misfold and aggregate, forming a spectrum of aggregate structures including oligomers and amyloid fibrils. To determine whether circulating nonnative TTR (NNTTR) levels correlate with the clinical status of patients with V30M TTR familial amyloid polyneuropathy (FAP), we quantified plasma NNTTR using a newly developed sandwich enzyme-linked immunosorbent assay. The assay detected significant plasma levels of NNTTR in most presymptomatic V30M TTR carriers and in all FAP patients. NNTTR was not detected in age-matched control plasmas or in subjects with other peripheral neuropathies, suggesting NNTTR can be useful in diagnosing FAP. NNTTR levels were substantially reduced in patients receiving approved FAP disease-modifying therapies (e.g., the TTR stabilizer tafamidis, 20 mg once daily). This NNTTR decrease was seen in both the responders (average reduction 56.4 ± 4.2%; n = 49) and nonresponders (average reduction of 63.3 ± 4.8%; n = 32) at 12 mo posttreatment. Notably, high pretreatment NNTTR levels were associated with a significantly lower likelihood of clinical response to tafamidis. Our data suggest that NNTTR is a disease driver whose reduction is sufficient to ameliorate FAP so long as pretreatment NNTTR levels are below a critical clinical threshold.

Acquired and inherited amyloidosis: Knowledge driving patients' care.

Until recently, systemic amyloidoses were regarded as ineluctably disabling and life-threatening diseases. However, this field has witnessed major advances in the last decade, with significant improvements in therapeutic options and in the availability of accurate and non-invasive diagnostic tools. Outstanding progress includes unprecedented hematological response rates provided by risk-adapted regimens in light chain (AL) amyloidosis and the approval of innovative pharmacological agents for both hereditary and wild-type transthyretin amyloidosis (ATTR). Moreover, the incidence of secondary (AA) amyloidosis has continuously reduced, reflecting advances in therapeutics and overall management of several chronic inflammatory diseases. The identification and validation of novel therapeutic targets has grounded on a better knowledge of key molecular events underlying protein misfolding and aggregation and on the increasing availability of diagnostic, prognostic and predictive markers of organ damage and response to treatment. In this review, we focus on these recent advancements and discuss how they are translating into improved outcomes. Neurological involvement dominates the clinical picture in transthyretin and gelsolin inherited amyloidosis and has a significant impact on disease course and management in all patients. Neurologists, therefore, play a major role in improving patients' journey to diagnosis and in providing early access to treatment in order to prevent significant disability and extend survival.

Editorial focus: understanding off-target effects as the key to successful RNAi therapy.

With the first RNA interference (RNAi) drug (ONPATTRO (patisiran)) on the market, we witness the RNAi therapy field reaching a critical turning point, when further improvements in drug candidate design and delivery pipelines should enable fast delivery of novel life changing treatments to patients. Nevertheless, ignoring parallel development of RNAi dedicated in vitro pharmacological profiling aiming to identify undesirable off-target activity may slow down or halt progress in the RNAi field. Since academic research is currently fueling the RNAi development pipeline with new therapeutic options, the objective of this article is to briefly summarize the basics of RNAi therapy, as well as to discuss how to translate basic research into better understanding of related drug candidate safety profiles early in the process.

Treatment of hereditary and acquired forms of transthyretin amyloidosis in the era of personalized medicine: the role of randomized controlled trials.

There have now been randomized controlled trials of four different therapeutics for hereditary amyloid polyneuropathy related to transthyretin (TTR) deposition and one for amyloidotic cardiomyopathy of both genetic and sporadic origin. It is likely that in the next few months those not already approved by either the US Food and Drug Administration (FDA) and/or the European Medicines Authority (EMA) will receive similar approvals for treatment for all or particular groups of patients. This is a far cry from circumstances less than 10 years ago when the only available therapy was gene replacement by liver transplant. The randomized controlled trials have shown that all the treatments (tafamidis, diflunisal, patisiran, and inotersen) are effective in the context of a clinical trial. However, we have very little idea of whether individual patients will respond in an equally positive way to all the drugs or whether there will be some who respond better to one or another or not respond at all, nor do we know whether combinations will be additive or synergistic. We lack validated markers of clinical response. While the small molecule TTR stabilizers increase serum TTR levels, the RNA-based drugs lower serum TTR. In the latter case, it is not clear that the reduction in serum TTR is related to the clinical response in a 1:1 fashion. Pharmaceutical companies have made substantial investments in the development of these agents and will clearly attempt to recoup those investments quickly. It is incumbent upon those of us who care for these patients to develop ways to assess the effects of therapy in the shortest possible time at the lowest possible cost. The better we are able to accomplish this the more likely it is that we will be able to treat the most patients in the most clinically efficient fashion regardless of their economic status. We now have the drugs we just have to figure out who should get them and when.

Tissue remodeling after interference RNA mediated knockdown of transthyretin in a familial amyloidotic polyneuropathy mouse model.

Transthyretin (TTR) deposition in the peripheral nervous system is the hallmark of familial amyloidotic polyneuropathy (FAP). Currently, liver transplantation is the only available treatment to halt the progression of clinical symptoms; however, due to the limitations of this procedure, development of alternative therapeutic strategies is of utmost importance. In this regard, interference RNA (RNAi) targeting TTR is currently in phase III clinical development. To dissect molecular changes occurring in dorsal root ganglia (DRG) upon RNAi-mediated knockdown of TTR, we treated both chronically and acutely an FAP mouse model, in different stages of disease. Our data show that inhibition of TTR expression by the liver with RNAi reverse TTR deposition in DRG, decrease matrix metalloproteinase-2 (MMP-2) protein levels in plasma, inhibit Mmp-2 gene expression and downregulate MMP-9 activity in DRG, indicating extracellular matrix remodeling. Furthermore, protein levels of MMP-2 were found upregulated in plasma samples from FAP patients indicating that MMP-2 might be a novel potential biomarker for FAP diagnosis. Collectively, our data show that silencing TTR liver synthesis in vivo can modulate TTR-induced pathology in the peripheral nervous system and highlight the potential of MMP-2 as a novel disease biomarker.

Clinical and prognostic differences among patients with light chain deposition disease, myeloma cast nephropathy and both.

In some patients with light chain deposition disease (LCDD) there is also evidence of myeloma cast nephropathy (MCN) on renal biopsy. The purpose of this study was to evaluate the renal and survival outcome of patients with concomitant diagnosis of MCN and LCDD to LCDD and MCN alone. Eighty seven patients were identified and divided into LCDD (n=45), MCN (n=29), and LCDD+ MCN (n=13). Patients with LCDD+ MCN had a worse overall survival (OS) compared to patients with LCDD (p=0.03), but similar to patients with MCN (p=0.4). Death-censored renal survival was no different amongst the groups. Presenting with acute renal failure at time of renal biopsy (HR 7.2, p=0.0002) was an independent poor renal prognostic factor while older age (HR 1.06, p=0.0002), presence of osteolytic lesions (HR 4.4, p<0.0001), and requirement for dialysis or creatinine≥5 mg/dL (HR 3.2, p=0.0006) at time of renal biopsy were independent poor prognostic factors for OS.

Current and future treatment of amyloid neuropathies.

Amyloid neuropathies of acquired or genetic origin are disabling and life-threatening, until recently there were few treatment options available. Poor prognosis is related to progressive neuropathy and associated, although often underdiagnosed, cardiac involvement in specific transthyretin (TTR) gene mutations. Recent progress has modified prognosis and management of amyloid neuropathies. In TTR-familial amyloidosis with polyneuropathy, major changes have occurred over the last 30 years: better knowledge concerning genetics, phenotypes and epidemiology, and the advent of possible treatments. Liver transplantation, first performed in 1990, stopped disease progression, thus doubling survival in early onset V30M patients. More recently tetramer stabilizers (Tafamidis and Diflunisal) showed a significant reduction of progression of neuropathic scores; Tafamidis is now recommended in Stage I patients. Two multicentric clinical trials are now ongoing to evaluate TTR gene silencing by antisense Oligonucleotides (ASO) or siRNA. In the near future we should have new therapeutical options for patients with amyloid neuropathy.

Amyloid neuropathies.

Peripheral neuropathy is a common complication of many of the systemic amyloidoses. Although the cause of neuropathy is not entirely clear, it is likely related to amyloid deposition within the nerve. This may lead to focal, multifocal, or diffuse neuropathies involving sensory, motor and/or autonomic fibers. The presenting symptoms depend on the distribution of nerves affected. One of the most common phenotypes is sensorimotor polyneuropathy, which is characterized by symptoms of neuropathic pain, numbness, and in advanced cases weakness. Symptoms begin in the feet and ultimately progress to the proximal legs and hands. The most common focal neuropathy is a median neuropathy at the wrist, clinically known as carpal tunnel syndrome. Carpal tunnel symptoms may include pain and sensory disturbances in the lateral palm and fingers; hand weakness may ensue if the focal neuropathy is severe. Autonomic neuropathy may affect a variety of organ systems such as the cardiovascular, gastrointestinal, and genitourinary systems. Symptoms may be non-specific making the diagnosis of autonomic neuropathy more difficult to identify. However, it is important to recognize and distinguish autonomic neuropathy from diseases of the end-organs themselves. This article reviews the inherited and acquired amyloidoses that affect the peripheral nervous system including familial amyloid polyneuropathy, and primary, secondary and senile amyloidosis. We emphasize the clinical presentation of the neurologic aspects of these diseases, physical examination findings, appropriate diagnostic evaluation, treatment and prognosis.

Amyloid neuropathies.

PURPOSE OF REVIEW: As amyloid neuropathies have benefited from recent major progress, this review is timely and relevant. RECENT FINDINGS: The main recent articles on amyloid neuropathy cover its description, methods for diagnosis and therapies. Varied clinical presentations are described in transthyretin (TTR)-familial amyloidosis with polyneuropathy (FAP) and light chain amyloid neuropathy. Mass spectrometry is able to identify the biochemical nature of amyloidogenic protein in nerve biopsy and skin biopsy samples for diagnosis of small fiber polyneuropathy. Both nerve biopsy and TTR gene sequencing are important to identify sporadic cases of amyloid neuropathy. Nerve biopsy is useful in demonstrating the amyloid origin of neuropathies developing after domino liver transplant recipients. Liver transplantation improves long-term survival in Met30 TTR-FAP. Factors recognized as leading to cardiomyopathy progression or heart involvement after liver transplantation are late disease onset and fibril composition. Combined heart and liver transplantation is recommended in severe restrictive cardiomyopathy. Antiamyloid drugs are emerging: tafamidis, a TTR stabilizer, showed in a phase III controlled study its ability to slow stage 1 FAP progression. Other strategies are emerging for TTR-FAP (combination doxycycline-tauroursodeoxycholic acid, small interfering RNA, antisense oligonucleotide, monoclonal antibody antiserum amyloid P component). For light chain neuropathy, intensive chemotherapy may be helpful. SUMMARY: There is better recognition of amyloid neuropathies, and hope for enrolling patients with FAP in future clinical trials testing new antiamyloid drugs.

[Original articles on axonal neuropathy in 2010]. / Les actualités sur les polyneuropathies axonales en 2010.

During 2010, 15 articles were published which focused on chronic sensorimotor axonal neuropathy; some will be discussed in this review. Clinical diagnosis from signs and symptoms seems to be excessively variable, often overestimating the incidence of diabetic sensorimotor polyneuropathy. Long-term use of Metformin is associated with malabsorption of vitamin B12. Metformin exposure may be a iatrogenic cause for exacerbation of peripheral neuropathy in patients with type 2 diabetes. The neuroprotective role of vitamin E against cisplatinperipheral neurotoxicity has been suggested by a phase III study. Metallosis after hip arthroplasty with a cobalt-chromium alloy prosthesis can cause progressive sensory disturbance, hearing loss and hypothyroidism. The effects of electrical stimulation on neuromuscular recovery after nerve crush injury in rats do not support a benefit of the tested protocol using electrical stimulation during the period of motor nerve recovery following injury. The rate of motor vehicle accidents in patients with neuropathy, based on surveys from 260 subjects, demonstrated that 40.6% were involved in traffic accidents. Accident frequency and discomfort with driving are higher in neuropathy patients compared to age-matched national statistics. Peripheral neuropathy in primary (AL) amyloidosis may be the cause of stepwise progressive, multiple upper limb mononeuropathies.

Cerebral AL lambda-amyloidoma: clinical and pathomorphological characteristics. Review of the literature and of a patient.

BACKGROUND: Amyloid deposits within the brain can be found in a heterogeneous group of diseases. Some of them involve only the central nervous system (AD); others are of systemic origin. Isolated deposits either in the brain, cranial nerves or within the spinal neural structures are extremely rare. So far, we do not know the natural origin, nor the clinical course. METHODS: We reviewed the overall published cases as far as available and added our own case to learn more about the natural history, clinical and imaging characteristics of this rare brain lesion. RESULTS: Together with our own case, 27 patients with cerebral amyloidoma were collected in the literature. The lesion always occurred supratentorially, moreover in another two cases also infratentorially. The initial symptoms as well as the results of different neuroimaging features were not specific. There was no predominance for sex and localization. Diagnosis could only be established by histopathological examination after surgical intervention. No recurrence was seen after radical resection; but there was progression in some cases of tumor biopsy. CONCLUSION: Complete surgical removal of cerebral AL amyloidoma seems to be the only way to prevent progression or recurrence of such a brain lesion.

A case of biopsy-proven leptomeningeal amyloidosis and intravenous Ig-responsive polyneuropathy associated with the Ala25Thr transthyretin gene mutation.

A growing body of literature has described familial leptomeningeal amyloidosis, a rare phenotype resulting from deposition of transthyretin (TTR) amyloid within the leptomeninges. We report herein the case of a patient with leptomeningeal amyloidosis presenting with hearing loss, asymmetrical polyneuropathy and sensory ataxia. This is the first Japanese case displaying TTR mutation at codon 25, replacing alanine with threonine. Neurophysiological examinations suggested demyelinating polyradiculoneuropathy, which improved dramatically after high-dose intravenous immunoglobulin treatment. Demyelinating polyneuropathy in our patient may be attributable to massive leptomeningeal amyloidosis, and no systemic organ involvement was identified. These characteristic clinical manifestations may have resulted from the Ala25Thr TTR gene mutation.

Axoval neuropathy as initial manifestation of primary amyloidosis: report of a case submitted to bone marrow transplantation.

Amyloidosis is a syndrome characterized by deposition of a highly insoluble protein material in the extracellular space that may affect several organs. It may be generalized and idiopathic (primary amyloidosis). We describe the case of a 48 years-old woman with axonal neuropathy associated with proteinuria, whose final investigation resulted in diagnosis of primary amyloidosis (AL). She was submitted to autologous bone marrow transplantation. We discuss some aspects related to diagnosis of neuropathy and current treatment of AL.

Targeted conversion of the transthyretin gene in vitro and in vivo.

Familial amyloidotic polyneuropathy (FAP) is the common form of hereditary generalized amyloidosis and is characterized by the accumulation of amyloid fibrils in the peripheral nerves and other organs. Liver transplantation has been utilized as a therapy for FAP, because the variant transthyretin (TTR) is predominantly synthesized by the liver, but this therapy is associated with several problems. Thus, we need to develop a new treatment that prevents the production of the variant TTR in the liver. In this study, we used HepG2 cells to show in vitro conversion of the TTR gene by single-stranded oligonucleotides (SSOs), embedded in atelocollagen, designed to promote endogenous repair of genomic DNA. For the in vivo portion of the study, we used liver from transgenic mice whose intrinsic wild-type TTR gene was replaced by the murine TTR Val30Met gene. The level of gene conversion was determined by real-time RCR combined with mutant-allele-specific amplification. Our results indicated that the level of gene conversion was approximately 11 and 9% of the total TTR gene in HepG2 cells and liver from transgenic mice, respectively. Gene therapy via this method may therefore be a promising alternative to liver transplantation for treatment of FAP.

Polineuropatía y miopatía del paciente crítico: ¿en qué hemos avanzado? / Polyneuropathy and myopathy in the critically ill. Where have we made progress?

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