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.

[Amyloid neuropathy resulting from an unknown protein]. / Neuropathie amyloïde liée à une protéine non identifiée.

Amyloid neuropathy is related to acquired or hereditary forms of amyloidosis resulting from transthyretin variants. We reported a 42-year-old man suffering from a peripheral neuropathy not related to transthyretin mutations. Mass spectrometry may be useful to identify this rare form of amyloid neuropathy.

Hereditary and acquired amyloid neuropathies.

Amyloid neuropathies occur in a context of hereditary (FAP) or acquired amyloidosis. They present usually as severe and progressive polyneuropathy and carry a poor prognosis. Most FAP are associated with endoneurial deposits of variant transthyretin (TTR) with substitution of one aminoacid and are secondary to a point mutation of the TTR gene. Portugal is the main endemic area of TTR-FAP, secondary to point mutation of exon 2. However, around the world, 50 other TTR gene mutations have been recently reported, each one in few families. Genetic studies are useful for diagnosis of FAP in patients with a positive family history and for identification of the cause of seemingly sporadic cases. TTR gene analysis is also useful for genetic counselling including antenatal diagnosis in variants with early onset. Gel-solin-FAP are the second variety and present as a benign cranial and sensory polyneuropathy and affect essentially Finnish patients. Acquired amyloid neuropathy concerns only immunoglobulin light chain amyloidosis (AL) and are frequently associated with renal manifestations and monoclonal protein in serum or urine. Specific treatment of amyloid polyneuropathy varies with the variety of amyloidosis including liver transplantation in TTR-FAP, at the onset of the disease or chemotherapy for immunoglobulin light chain amyloidosis.

[Classification of amyloidosis]. / Klassifisering av amyloidose.

Amyloidosis is a collective term for a heterogeneous group of disorders characterized by deposition of a fibrillar, proteinaceous material, amyloid, in various tissues and organs. Increasing knowledge about the different proteins that constitute the amyloid fibrils has made it possible to classify amyloidosis by the fibril protein, which appears more rational than the traditional classification by its clinical symptoms. A group of experts on amyloidosis met in Oslo in 1990 and agreed upon a nomenclature and classification based on the chemical properties of the amyloid fibrils.

Systemic amyloidosis in transgenic mice carrying the human mutant transthyretin (Met 30) gene. Pathological and immunohistochemical similarity to human familial amyloidotic polyneuropathy, type I.

To analyze the pathologic processes of amyloid deposition in type I familial amyloidotic polyneuropathy (FAP), mice were made transgenic by introducing the human mutant transthyretin (TTR) gene(MT-hMet 30). An inbred strain of mouse, C57 BL/6, was chosen. Transgenic mice were killed using ether anesthesia at 3-mo intervals up to 24 mo after birth. In these transgenic mice, amyloid deposition started in the gastrointestinal tract, cardiovascular system, and kidneys and extended to various other organs and tissues with advancing age. The pattern of amyloid deposition was similar to that observed in human autopsy cases of FAP, except for its absence in the choroid plexus and in the peripheral and autonomic nervous systems. We extracted the amyloid fibrils from kidneys of these mice with a human mutant TTR gene and analyzed them immunochemically and electronmicroscopically. Deposited amyloid was shown to be composed of human mutant TTR and mouse serum amyloid P component. Amyloid fibril from transgenic mice was morphologically and immunohistochemically similar to that of human FAP. The most striking pathologic feature of the transgenic mice was the absence of amyloid deposition in the peripheral and autonomic nervous tissues. Thus, other intrinsic factors may be involved in amyloid deposition in the nervous tissues of human FAP.

[Clinical and genetic heterogeneity in familial amyloidotic polyneuropathy associated with variant transthyretin].

Familial amyloid polyneuropathy (FAP) is an autosomal disease, usually associated with a variant of transthyretin (TTR). To date, about 30 variants of TTR have been described in FAP. Clinical heterogeneity regarding age of onset and organ involvement exists in TTR-related FAP. The age of onset in patients with TTR-Met 30 variant ranges from the third to the seventh decade. The pattern of peripheral neuropathy varies considerably. Lower limb neuropathy is the common mode in cases with Met 30 and other many variants of TTR, while in some cases, upper limb neuropathy with carpal tunnel syndrome is the most important feature. The presence of vitreous opacity is one of the cardinal manifestations in several kindreds (eg. Cys 114, lle 33). The mechanism by which variant TTR affects clinical heterogeneity in FAP is unknown and deserves future study.