Clinical Features of Familial Amyloidotic Polyneuropathy With Transthyretin p.Ala117Ser Mutation in Mainland China

Objective: Our study aimed to report the clinical features of ATTR-PN with TTR p.Ala117Ser mutation in mainland China. Methods: Thirteen patients from 13 different families diagnosed with p.Ala117Ser ATTR-PN were identified from three centres. Clinical and laboratory data were retrospectively retrieved for analysis. Results: The male/female ratio was 11:2. All patients showed late onset, with the age of onset at 57.8 ± 5.8 years. The initial symptom was numbness of the lower or upper extremities in 9 patients (69.2%). Paraesthesia was present in all patients. Eleven patients (84.6%) had autonomic dysfunction. Cardiac, renal, hepatic, and ocular dysfunctions were noted in 8 (61.5%), 1 (7.7%), 2 (15.4%), and 3 (23.1%) patients, respectively. Nerve conduction studies have shown axonal-type sensorimotor polyneuropathy. The decline in sensory nerve action potentials was more noticeable than in compound muscle action potentials. The nerve damage present in the lower limbs was more severe than that in the upper limbs. Nerve biopsy revealed positive Congo red staining in 7/10 patients (70%). Conclusion: Our study is the largest population report on this rare p.Ala117Ser mutation in mainland China.

Use of Drugs for ATTRv Amyloidosis in the Real World: How Therapy Is Changing Survival in a Non-Endemic Area

Background: Over the past decade, three new drugs have been approved for the treatment of hereditary amyloid transthyretin (ATTRv) polyneuropathy. The aim of this work was to analyze whether current therapies prolong survival for patients affected by ATTRv amyloidosis. Methods: The study was conducted retrospectively, analyzing the medical records of 105 patients with genetic diagnoses of familial amyloidotic polyneuropathy followed at the two referral centers for the disease in Sicily, Italy. Of these, 71 received disease-modifying therapy, while 34 received only symptomatic treatment or no therapy. Results: The most used treatment in our patient cohort was tafamidis, followed by liver transplantation, patisiran, inotersen, and diflunisal. The median survival was significantly longer for treated vs. untreated patients (12 years vs. 8 years). In the 71 patients who received disease-modifying treatment, the presence of cardiac involvement, weight loss, or autonomic dysfunction at diagnosis was not related to survival. Conversely, patients diagnosed in the early stage of the disease (PND 1) had significantly longer survival than those diagnosed in the late stage (PND 2–4).

Preparative Scale Production of Recombinant Human Transthyretin for Biophysical Studies of Protein-Ligand and Protein-Protein Interactions

Human transthyretin (hTTR), a serum protein with a main role in transporting thyroid hormones and retinol through binding to the retinol-binding protein, is an amyloidogenic protein involved in familial amyloidotic polyneuropathy (FAP), familial amyloidotic cardiomyopathy, and central nervous system selective amyloidosis. hTTR also has a neuroprotective role in Alzheimer disease, being the major Aβ binding protein in human cerebrospinal fluid (CSF) that prevents amyloid-β (Aβ) aggregation with consequent abrogation of toxicity. Here we report an optimized preparative expression and purification protocol of hTTR (wt and amyloidogenic mutants) for in vitro screening assays of TTR ligands acting as amyloidogenesis inhibitors or acting as molecular chaperones to enhance the TTR:Aβ interaction. Preparative yields were up to 660 mg of homogenous protein per L of culture in fed-batch bioreactor. The recombinant wt protein is mainly unmodified at Cys10, the single cysteine in the protein sequence, whereas the highly amyloidogenic Y78F variant renders mainly the S-glutathionated form, which has essentially the same amyloidogenic behavior than the reduced protein with free Cys10. The TTR production protocol has shown inter-batch reproducibility of expression and protein quality for in vitro screening assays.

Neuropathies

Peripheral neuropathies are most frequently a complication of a variety of acute and chronic diseases and injuries, including diseases of the roots, plexuses, and peripheral nerves in various combinations, and are categorized as symmetric polyneuropathies, mononeuropathies, multifocal neuropathies, and radiculopathies. This chapter illustrates data about peripheral neuropathies in the general population and in selected cohorts at risk: diabetic neuropathy (present in 66% of insulin-dependent and 59% of non-insulin-dependent diabetic individuals), acute and chronic inflammatory (2–16% of all polyneuropathies in hospital-based studies), paraneoplastic, infectious (Mycobacterium leprae, HIV, predominant in resource-poor countries), toxic and iatrogenic (antibacterial, antiparasitic, cardiovascular and chemotherapeutic agents), due to entrapment (carpal tunnel syndrome), and inherited (Charcot-Marie-Tooth, familial amyloidotic polyneuropathy, hereditary motor/sensory neuropathies). The actual burden of peripheral neuropathies is unknown because incidence and prevalence are preferably calculated in patients with the underlying cause and for the variability and low validity and reliability of the diagnostic criteria.

A 5-Year Follow-Up of The Benefits of an Exercise Training Program in Liver Recipients Transplanted Due to Familial Amyloidotic Polyneuropathy

Background: Supervised (SE) and home-based exercise (HBE) training regimes are effective on reconditioning patients with familial amyloidotic polyneuropathy (FAP) after liver transplantation, but research of the long-term retention of the benefits attained in patients with FAP has not yet been conducted. Purpose: In this 5-year follow-up study, we aimed to determine whether the exercise training gains in body composition, physical activity, and function promoted by a 24-week SE or HBE training regimes are retained in patients with FAP who resume normal activity. Methodology: Sixteen liver-transplanted patients with FAP were reassessed for body composition (dual X-ray absorptiometry), physical activity (questionnaire), and function (handgrip strength and 6-minute walk test). Results: Total body fat increased with both exercise regimes during follow-up ( P < .05; η2 = 0.432-0.625) as well as femoral neck bone density ( P = .048; η2 = 0.119). However, gains in upper limbs muscle quality during follow-up ( P < .001; η2 = 0.597) were only found in the SE group ( P = .042; η2 = 0.245). Both exercise regimes showed retaining aptitudes in walking capacity ( P < .05; η2 = 0.329-0.460) and muscle mass ( P = .05; η2 = 0.245). Still, none could retain the physical activity levels. Conclusion: Long-term resumption of normal activity following a 24-week SE or HBE regime in patients with FAP resulted in loss of exercise induced increases in physical activity but counterweighted postoperative losses in bone mineral density and substantially retained the benefits in walking capacity, muscle mass, and quality, in particular, in the SE group.