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Advances in Experimental Medicine and... 2019Transthyretin (TTR)-familial amyloid polyneuropathy (FAP) is a systemic amyloidosis caused by mutations in the TTR gene. Typically, patients initially present with... (Review)
Review
Transthyretin (TTR)-familial amyloid polyneuropathy (FAP) is a systemic amyloidosis caused by mutations in the TTR gene. Typically, patients initially present with sensory and autonomic symptoms, which can lead to sensory dominant polyneuropathy and autonomic neuropathy. Mutations in TTR cause the tetrameric protein to dissociate and form amyloid deposits in the peripheral nervous system, most prominently in dorsal root ganglia (DRG), autonomic ganglia, and nerve trunks. Teased fiber studies have shown that segmental demyelination and axonal degeneration preferentially occur in the proximal and distal regions of the peripheral nerves, respectively. Nevertheless, it remains unknown why genetic variants of TTR lead to neurodegeneration in the peripheral nervous system. Recent studies in our laboratory have uncovered an important role for Schwann cells in the disease progression of FAP. In this review, we summarize findings implicating Schwann cells in FAP, and provide evidence that DRG may serve as the initial site of lesion formation in the disease.
Topics: Amyloid; Amyloid Neuropathies, Familial; Axons; Demyelinating Diseases; Ganglia, Spinal; Humans; Prealbumin; Schwann Cells
PubMed: 31760657
DOI: 10.1007/978-981-32-9636-7_24 -
Practical Neurology Jun 2019Systemic amyloidosis can be hereditary or acquired. The autosomal dominant hereditary transthyretin amyloidosis and the acquired light-chain amyloidosis, the result of a... (Review)
Review
Systemic amyloidosis can be hereditary or acquired. The autosomal dominant hereditary transthyretin amyloidosis and the acquired light-chain amyloidosis, the result of a plasma cell dyscrasia, are multisystem disorders with cardiovascular, autonomic and peripheral nerve involvement. There are numerous investigational modalities available to diagnose systemic amyloidosis and to assess the extent of organ involvement, but it is frequently misdiagnosed due to its heterogeneous clinical presentations and misleading investigation findings. An accurate and timely diagnosis of amyloid neuropathy can greatly impact on the outcomes for patients, especially as there will soon be new gene-silencing treatments for hereditary transthyretin amyloidosis.
Topics: Aged; Amyloid; Amyloid Neuropathies; Amyloid Neuropathies, Familial; Amyloidosis; Female; Humans; Peripheral Nerves; Prealbumin
PubMed: 30598431
DOI: 10.1136/practneurol-2018-002098 -
Seminars in Neurology Oct 2019Peripheral neuropathy occurs in the setting of both hereditary and acquired amyloidosis. The most common form of hereditary amyloidosis is caused by 1 of 140 mutations... (Review)
Review
Peripheral neuropathy occurs in the setting of both hereditary and acquired amyloidosis. The most common form of hereditary amyloidosis is caused by 1 of 140 mutations in the transthyretin (TTR) gene, which can lead to neuropathic hereditary transthyretin amyloidosis (hATTR; previously referred to as transthyretin familial amyloid polyneuropathy), whereas acquired immunoglobulin light chain (AL) amyloidosis is the most common acquired form. Patients typically present with a sensorimotor polyneuropathy, focal neuropathy such as carpal tunnel syndrome, or autonomic neuropathy. When neuropathy is the sole or dominant presenting symptom, the diagnosis is commonly delayed. With the advent of new drug therapies for AL amyloidosis and hATTR amyloidosis, including proteasome inhibitors, TTR silencers, and TTR protein stabilizers, the neurologist is uniquely positioned to diagnose neurologic manifestations of systemic amyloidosis, leading to earlier disease identification and treatment. This article reviews the epidemiology, clinical presentations, pathophysiology, diagnostic workup, and treatment of neuropathy in the setting of amyloidosis.
Topics: Amyloid Neuropathies, Familial; Humans; Immunoglobulin Light-chain Amyloidosis; Mutation; Nervous System Diseases; Prealbumin
PubMed: 31639841
DOI: 10.1055/s-0039-1688994 -
Current Opinion in Neurology Oct 2012As amyloid neuropathies have benefited from recent major progress, this review is timely and relevant. (Review)
Review
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.
Topics: Amyloid Neuropathies; Amyloidosis, Familial; Animals; Endemic Diseases; Humans; Liver Transplantation; Prealbumin
PubMed: 22941262
DOI: 10.1097/WCO.0b013e328357bdf6 -
Journal of Neurology Jun 2021Amyloid transthyretin (ATTR) amyloidosis with polyneuropathy (PN) is a progressive, debilitating, systemic disease wherein transthyretin protein misfolds to form... (Review)
Review
Amyloid transthyretin (ATTR) amyloidosis with polyneuropathy (PN) is a progressive, debilitating, systemic disease wherein transthyretin protein misfolds to form amyloid, which is deposited in the endoneurium. ATTR amyloidosis with PN is the most serious hereditary polyneuropathy of adult onset. It arises from a hereditary mutation in the TTR gene and may involve the heart as well as other organs. It is critical to identify and diagnose the disease earlier because treatments are available to help slow the progression of neuropathy. Early diagnosis is complicated, however, because presentation may vary and family history is not always known. Symptoms may be mistakenly attributed to other diseases such as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), idiopathic axonal polyneuropathy, lumbar spinal stenosis, and, more rarely, diabetic neuropathy and AL amyloidosis. In endemic countries (e.g., Portugal, Japan, Sweden, Brazil), ATTR amyloidosis with PN should be suspected in any patient who has length-dependent small-fiber PN with autonomic dysfunction and a family history of ATTR amyloidosis, unexplained weight loss, heart rhythm disorders, vitreous opacities, or renal abnormalities. In nonendemic countries, the disease may present as idiopathic rapidly progressive sensory motor axonal neuropathy or atypical CIDP with any of the above symptoms or with bilateral carpal tunnel syndrome, gait disorders, or cardiac hypertrophy. Diagnosis should include DNA testing, biopsy, and amyloid typing. Patients should be followed up every 6-12 months, depending on the severity of the disease and response to therapy. This review outlines detailed recommendations to improve the diagnosis of ATTR amyloidosis with PN.
Topics: Adult; Amyloid Neuropathies, Familial; Brazil; Consensus; Humans; Japan; Polyneuropathies; Portugal; Prealbumin; Sweden
PubMed: 31907599
DOI: 10.1007/s00415-019-09688-0 -
Acta Neurologica Taiwanica Jun 2011Familial amyloid polyneuropathy (FAP) is a major etiology in differential diagnosis of symmetric axonalform polyneuropathy, but had been considered an unusual disease in... (Review)
Review
Familial amyloid polyneuropathy (FAP) is a major etiology in differential diagnosis of symmetric axonalform polyneuropathy, but had been considered an unusual disease in Taiwan. We have reviewed the pathology of nerve biopsies and sequenced the entire 4 exons of transthyretin (TTR), the most common genetic mutation of FAP. Our studies indicated that the mutation of TTR at Ala97Ser (TTR Ala97Ser) was a new mutation only reported in ethnic Taiwanese, and this mutation accounted for the most frequent etiology of adult-onset pan-modality (involving motor, sensory, and autonomic components of peripheral nerves) polyneuropathy with the pathology of axonal degeneration type. Over the past 10 years, there have been advancements in the management of FAP due to TTR mutations: (1) symptomatic treatments of dyaautonomia, especially orthostatic hypotension, and (2) therapies with liver transplantation and small molecules to reduce or stabilize TTR.
Topics: Age of Onset; Alanine; Amyloid Neuropathies; Female; Genetic Predisposition to Disease; Humans; Male; Mutation; Prealbumin; Serine; Sex Factors; Taiwan
PubMed: 21739396
DOI: No ID Found -
The Lancet. Neurology Nov 2023Hereditary transthyretin (TTR) amyloid polyneuropathy is an autosomal dominant life-threatening disorder. TTR is produced mainly by the liver but also by the choroid... (Review)
Review
Hereditary transthyretin (TTR) amyloid polyneuropathy is an autosomal dominant life-threatening disorder. TTR is produced mainly by the liver but also by the choroid plexus and retinal pigment epithelium. Detailed clinical characterisation, identification of clinical red flags for misdiagnosis, and use of biomarkers enable early diagnosis and treatment. In addition to liver transplantation and TTR stabilisers, three other disease-modifying therapies have regulatory approval: one antisense oligonucleotide (inotersen) and two small interfering RNAs (siRNAs; patisiran and vutrisiran). The siRNAs have been shown to stop progression of neuropathy and improve patients' quality of life. As none of the disease-modifying therapies can cross the blood-brain barrier, TTR deposition in the CNS, which can cause stroke and cognitive impairment, remains an important unaddressed issue. CRISPR-Cas9-based one-time TTR editing therapy is being investigated in a phase 1 clinical study. Identification of the earliest stages of pathogenesis in TTR variant carriers is a major challenge that needs addressing for optimal management.
Topics: Humans; Amyloid Neuropathies, Familial; Prealbumin; Quality of Life; Amyloid Neuropathies; Biomarkers
PubMed: 37863593
DOI: 10.1016/S1474-4422(23)00334-4 -
AH amyloid neuropathy: a novel clinical phenotype confirmed by histopathology and mass spectrometry.Amyloid : the International Journal of... Jun 2022
Topics: Amyloid Neuropathies; Humans; Mass Spectrometry; Phenotype
PubMed: 35285361
DOI: 10.1080/13506129.2022.2049745 -
Journal of Neurology, Neurosurgery, and... Jun 2022Hereditary transthyretin amyloidosis (ATTRv) is a severe, adult-onset autosomal dominant inherited systemic disease predominantly affecting the peripheral and autonomic... (Review)
Review
Hereditary transthyretin amyloidosis (ATTRv) is a severe, adult-onset autosomal dominant inherited systemic disease predominantly affecting the peripheral and autonomic nervous system, heart, kidney and the eyes. ATTRv is caused by mutations of the transthyretin (TTR) gene, leading to extracellular deposition of amyloid fibrils in multiple organs including the peripheral nervous system. Typically, the neuropathy associated with ATTRv is characterised by a rapidly progressive and disabling sensorimotor axonal neuropathy with early small-fibre involvement. Carpal tunnel syndrome and cardiac dysfunction frequently coexist as part of the ATTRv phenotype. Although awareness of ATTRv polyneuropathy among neurologists has increased, the rate of misdiagnosis remains high, resulting in significant diagnostic delays and accrued disability. A timely and definitive diagnosis is important, given the emergence of effective therapies which have revolutionised the management of transthyretin amyloidosis. TTR protein stabilisers diflunisal and tafamidis can delay the progression of the disease, if treated early in the course. Additionally, TTR gene silencing medications, patisiran and inotersen, have resulted in up to 80% reduction in TTR production, leading to stabilisation or slight improvement of peripheral neuropathy and cardiac dysfunction, as well as improvement in quality of life and functional outcomes. The considerable therapeutic advances have raised additional challenges, including optimisation of diagnostic techniques and management approaches in ATTRv neuropathy. This review highlights the key advances in the diagnostic techniques, current and emerging management strategies, and biomarker development for disease progression in ATTRv.
Topics: Amyloid Neuropathies, Familial; Heart Diseases; Humans; Polyneuropathies; Prealbumin; Quality of Life
PubMed: 35256455
DOI: 10.1136/jnnp-2021-327909 -
The Mount Sinai Journal of Medicine,... 2012Peripheral 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... (Review)
Review
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.
Topics: Age Factors; Amyloid Neuropathies; Amyloid Neuropathies, Familial; Combined Modality Therapy; Humans; Physical Examination; Prognosis; Risk Factors
PubMed: 23239211
DOI: 10.1002/msj.21352