Corneal sub-basal whorl-like nerve plexus: a landmark for early and follow-up evaluation in transthyretin familial amyloid polyneuropathy.

BACKGROUND AND PURPOSE: Small-fiber nerves are the first to be involved in transthyretin familial amyloid polyneuropathy (TTR-FAP) patients. In vivo corneal confocal microscopy (CCM) is a noninvasive technique to detect small-fiber polyneuropathy (SFN) by quantifying corneal nerve morphology. The characteristic whorl-like pattern of the corneal nerve provides a static landmark for observation. We aimed to evaluate whether CCM images of the whorl-like plexus can sensitively evaluate and monitor disease progression in FAP patients. METHODS: Fifteen FAP patients and 15 controls underwent neurological evaluation and CCM observation. Corneal nerve fiber length (CNFL), corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD) detected by conventional method and inferior whorl length (IWL), inferior whorl fiber density (IWFD), and inferior whorl branch density (IWBD) were compared in controls and patients. The Langerhans cell (LC) density in each image was calculated. RESULTS: All CCM parameters were significantly reduced with disease progression. Preclinical patients had significantly lower IWL (P = 0.008) than age-matched controls. IWL (P = 0.006), CNFL (P = 0.005), CNBD (P = 0.008), and CNFD (P = 0.014) were significantly lower in early-phase patients. LC density was significantly increased around the central whorl in early-phase patients and was relatively lower in progressive patients. Both IWL and CNFL correlated with the severity of neuropathy, and IWL was more significantly reduced. The area under the receiver operating characteristic (ROC) curve for FAP with CNFL and IWL was 88.0% (95% CI, 70.9%-96.9%) and 89.3% (95% CI, 72.6%-97.6%), respectively, exceeding other parameters. CONCLUSIONS: IWL is a more sensitive surrogate to detect preclinical SFN in FAP and can best discriminate patients from controls. The clustering of immature LCs at the inferior whorl area might reflect the inflammatory response of small-fiber nerves at the early stage.

Nerve ultrasonography findings as possible pitfall in differential diagnosis between hereditary transthyretin amyloidosis with polyneuropathy and chronic inflammatory demyelinating polyneuropathy.

Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is a rare form of treatable severe progressive sensory-motor and autonomic polyneuropathy. Albeit usually axonal, late-onset ATTRv-PN can show clear demyelinating features at electrodiagnostic studies, sometimes fulfilling CIDP diagnostic criteria. High-resolution nerve ultrasonography (HRUS) is an emerging useful supportive tool in the diagnosis of CIDP. Herein, we present a late-onset ATTRv-PN patient in which both clinical-neurophysiological and HRUS features could have led to a CIDP misdiagnosis. Nerve alterations at HRUS and MRI have already been reported in ATTRv-PN, albeit not in ATTRv-PN patients with clinical and electrodiagnostic features of CIDP. Our case shows that ATTRv-PN could present the same morphological nerve alterations pattern of CIDP at ultrasonography, adding HRUS findings as a further source of misdiagnosis late-onset ATTRv-PN.

Epidemiology of Transthyretin Familial Amyloid Polyneuropathy in Portugal: A Nationwide Study.

BACKGROUND: Transthyretin-associated familial amyloid polyneuropathy (TTR-FAP) is a rare, hereditary, progressive and neurodegenerative disease. We aimed to study -TTR-FAP epidemiology in Portugal. METHODS: National, observational, prospective and retrospective, case identification of adults with TTR-FAP. Countrywide patient multiple identification sources included reference centers registries and centralized medical electronic prescription database. Crude rates were reported per 100,000 adult inhabitants. RESULTS: Over 2010-2016 period, mean incidence rates was 0.87/100,000 (95% CI 0.68-1.10) corresponding to 71 new patients yearly, that has decreased 31% in the last 7 years. The proportion of late-onset cases (age ≥50 years) among incident cases was 28.7%. Estimated crude 2016 prevalence was 22.93/100,000 adult inhabitants (95% CI 21.90-23.99) corresponding to 1,865 TTR-FAP individuals in Portugal (45.8% male; mean age: 52.3 ± 15.4 years). In 2016, the Portuguese region with the highest TTR-FAP prevalence shows a 16% prevalence increase over the last 25 years. CONCLUSIONS: In Portugal, TTR-FAP affects both genders and mainly young adults. TTR-FAP incidence appears to be decreasing while prevalence is increasing. In comparison to previous studies, there is an increased representativeness of late-onset patients. This epidemiological setting poses future and complex challenges for the social and healthcare system, strengthening the relevance of regular epidemiologic surveillance.

Estimating the global prevalence of transthyretin familial amyloid polyneuropathy.

INTRODUCTION: This study sought to estimate the global prevalence of transthyretin familial amyloid polyneuropathy (ATTR-FAP). METHODS: Prevalence estimates and information supporting prevalence calculations was extracted from records yielded by reference-database searches (2005-2016), conference proceedings, and nonpeer reviewed sources. Prevalence was calculated as prevalence rate multiplied by general population size, then extrapolated to countries without prevalence estimates but with reported cases. RESULTS: Searches returned 3,006 records; 1,001 were fully assessed and 10 retained, yielding prevalence for 10 "core" countries, then extrapolated to 32 additional countries. ATTR-FAP prevalence in core countries, extrapolated countries, and globally was 3,762 (range 3639-3884), 6424 (range, 1,887-34,584), and 10,186 (range, 5,526-38,468) persons, respectively. DISCUSSION: The mid global prevalence estimate (10,186) approximates the maximum commonly accepted estimate (5,000-10,000). The upper limit (38,468) implies potentially higher prevalence. These estimates should be interpreted carefully because contributing evidence was heterogeneous and carried an overall moderate risk of bias. This highlights the requirement for increasing rare-disease epidemiological assessment and clinician awareness. Muscle Nerve 57: 829-837, 2018.

In vivo detection of nerve injury in familial amyloid polyneuropathy by magnetic resonance neurography.

Transthyretin familial amyloid polyneuropathy is a rare, autosomal-dominant inherited multisystem disorder usually manifesting with a rapidly progressive, axonal, distally-symmetric polyneuropathy. The detection of nerve injury by nerve conduction studies is limited, due to preferential involvement of small-fibres in early stages. We investigated whether lower limb nerve-injury can be detected, localized and quantified in vivo by high-resolution magnetic resonance neurography. We prospectively included 20 patients (12 male and eight female patients, mean age 47.9 years, range 26-66) with confirmed mutation in the transthyretin gene: 13 with symptomatic polyneuropathy and seven asymptomatic gene carriers. A large age- and sex-matched cohort of healthy volunteers served as controls (20 male and 20 female, mean age 48.1 years, range 30-73). All patients received detailed neurological and electrophysiological examinations and were scored using the Neuropathy Impairment Score-Lower Limbs, Neuropathy Deficit and Neuropathy Symptom Score. Magnetic resonance neurography (3 T) was performed with large longitudinal coverage from proximal thigh to ankle-level and separately for each leg (140 axial slices/leg) by using axial T2-weighted (repetition time/echo time = 5970/55 ms) and dual echo (repetition time 5210 ms, echo times 12 and 73 ms) turbo spin echo 2D sequences with spectral fat saturation. A 3D T2-weighted inversion-recovery sequence (repetition time/echo time 3000/202 ms) was acquired for imaging of the spinal nerves and lumbar plexus (50 axial slice reformations). Precise manual segmentation of the spinal/sciatic/tibial/common peroneal nerves was performed on each slice. Histogram-based normalization of nerve-voxel signal intensities was performed using the age- and sex-matched control group as normative reference. Nerve-voxels were subsequently classified as lesion-voxels if a threshold of >1.2 (normalized signal-intensity) was exceeded. At distal thigh level, where a predominant nerve-lesion-voxel burden was observed, signal quantification was performed by calculating proton spin density and T2-relaxation time as microstructural markers of nerve tissue integrity. The total number of nerve-lesion voxels (cumulated from proximal-to-distal) was significantly higher in symptomatic patients (20 405 ± 1586) versus asymptomatic gene carriers (12 294 ± 3199; P = 0.036) and versus controls (6536 ± 467; P < 0.0001). It was also higher in asymptomatic carriers compared to controls (P = 0.043). The number of nerve-lesion voxels was significantly higher at thigh level compared to more distal levels (lower leg/ankle) of the lower extremities (f-value = 279.22, P < 0.0001). Further signal-quantification at this proximal site (thigh level) revealed a significant increase of proton-density (P < 0.0001) and T2-relaxation-time (P = 0.0011) in symptomatic patients, whereas asymptomatic gene-carriers presented with a significant increase of proton-density only. Lower limb nerve injury could be detected and quantified in vivo on microstructural level by magnetic resonance neurography in symptomatic familial amyloid polyneuropathy, and also in yet asymptomatic gene carriers, in whom imaging detection precedes clinical and electrophysiological manifestation. Although symptoms start and prevail distally, the focus of predominant nerve injury and injury progression was found proximally at thigh level with strong and unambiguous lesion-contrast. Imaging of proximal nerve lesions, which are difficult to detect by nerve conduction studies, may have future implications also for other distally-symmetric polyneuropathies.

Anesthesia management of combined sequential heart-liver transplantation using a caval clamp without venovenous bypass: A case report.

Familial amyloid polyneuropathy, an autosomal-dominant disease due to mutations in the transthyretin gene, often affects the heart and liver, and is treated best with a combined heart-liver transplantation (CHLT). Although it remains an uncommonly performed procedure, the number of patients undergoing CHLT is increasing. Because of the complexity associated with dual pathophysiology, CHLT poses an extraordinary challenge for anesthesia management. Either both heart and liver transplantation are performed on cardiopulmonary bypass (CPB); or heart transplantation is performed on CPB, followed by liver transplantation with venovenous bypass. Recent reports suggested that liver transplantation can be performed without bypass using the inferior vena cava-sparing technique. However, both bypass and caval sparing technique have their own complications. Here, we present the anesthesia management in a case of sequential heart-liver transplantation using a routine caval cross-clamp technique without venovenous bypass. A 48-year-old man complaining of chest tightness, chest pain, and shortness of breath was diagnosed with amyloid cardiomyopathy. Cardiac ultrasonography revealed thickening of ventricular walls and left ventricular systolic insufficiency (ejection fraction decreased from 46% to ∼20% in 6 months), which was refractory to medical therapy. Symptoms occurred repeatedly. Therefore, CHLT was planned. Heart transplantation was performed smoothly under general anesthesia and standard CPB. His heart functioned well with dobutamine and epinephrine infusion. Subsequently, the patient was weaned from CPB. Liver transplantation was planned using the piggyback procedure with the caval sparing technique. However, upon caval clamping, unexpected blood loss occurred. Clamping of the caval was tested followed by cross-clamping. Norepinephrine, epinephrine, and dobutamine were administered. After the hepatic vein was anastomosed, the clamp was released and nitroglycerin was administered. Hemodynamics was stable, and the patient was discharged after 37 days of hospitalization. The case indicates that CHLT could be performed using caval clamp without venovenous bypass in selected patients.

Conjunctival lymphangiectasia and retinal angiopathy in hereditary transthyretin amyloidosis.

BACKGROUND: Hereditary transthyretin amyloidosis (ATTR amyloidosis) is a rare condition where a mutation in the transthyretin gene leads to systemic deposition of amyloid. The manifestations and prognosis of ATTR amyloidosis depends on the specific ATTR mutation, with over 100 mutations reported in the literature. The manifestations of many rare forms of ATTR amyloidosis have not been well described, particularly the late-onset ophthalmic findings. CASE PRESENTATION: We present the case of a 43-year-old Caucasian male with a diagnosis of ATTRD18E amyloidosis confirmed by fat pad biopsy. He had diffuse systemic involvement, including cardiovascular, pulmonary, and gastrointestinal symptoms. He also had significant ocular involvement including vitreous opacities, retinal angiopathy, and conjunctival lymphangiectasia. These ocular findings modestly progressed at 2-year follow-up. DISCUSSION: The ATTRD18E mutation is a rare variant, with few described cases. To our knowledge, this is the first documented case of ATTRD18E amyloidosis with significant ocular involvement. These ocular findings may serve as a relevant biomarker for severe disease prognosis in ATTRD18E amyloidosis. With improving treatments addressing the systemic symptoms of ATTR amyloidosis, a better understanding of the late-onset ocular symptoms is becoming increasingly relevant.

Quantitative sudomotor test helps differentiate transthyretin familial amyloid polyneuropathy from chronic inflammatory demyelinating polyneuropathy.

OBJECTIVE: Transthyretin familial amyloid polyneuropathy (TTR-FAP) is an aggressive hereditary neuropathy characterized by sensory and autonomic dysfunction. There are numerous reports of TTR-FAP misdiagnosed and treated as chronic inflammatory demyelinating polyneuropathy (CIDP), leading to delayed diagnosis, risk of iatrogenic adverse events and increased socio-economic costs. Quantitative sudomotor function measured by electrochemical skin conductance (ESC) appears to be a sensitive test in TTR-FAP. We aimed to evaluate the performance of ESC in differentiating TTR-FAP from CIDP. METHODS: Thirty-eight patients with genetically confirmed hereditary TTR amyloidosis and 26 with definite CIDP according to the EFNS/PNS guidelines and negative TTR-FAP genetic testing were involved in this study. We compared the ESC for feet and hands measured by Sudoscan for each patient. RESULTS: ESC (µS) was significantly lower in TTR-FAP for both hands (72 vs 45, p < 0.0001) and feet (77 vs 35, p < 0.0001). Feet ESC < 64 µS had a 89% sensitivity and a 96% specificity to differentiate between CIDP and TTR-FAP. CONCLUSION: Sudoscan is a fast, non-invasive and easy to perform test, able to distinguish CIDP and TTR-FAP patients with good sensitivity and specificity. SIGNIFICANCE: Sudoscan can be helpful in distinguishing between CIDP and TTR-FAP.

Amyloid Cardiomyopathy in the Rare Transthyretin Tyr78Phe Mutation.

Tyr78Phe is a rare pathogenic transthyretin (TTR) mutation. Few previous reports described a late-onset hereditary transthyretin-related amyloidosis (ATTR-m) form with a variable phenotype, mainly dominated by neurological manifestations. We describe the case of a 69-year-old male with massive but asymptomatic cardiac infiltration and only subclinical neurological involvement, and review the literature to depict characteristics of the Tyr78Phe TTR mutation.

Electrophysiological demyelinating features in hereditary ATTR amyloidosis.

OBJECTIVE: To elucidate the electrophysiological demyelinating features in patients with hereditary ATTR amyloidosis that may lead to a misdiagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: In 102 patients with hereditary ATTR amyloidosis (85 Val30Met and 17 non-Val30Met; 37 and 65 from endemic and non-endemic areas, respectively), results of motor nerve conduction studies (MNCSs) with a 2-Hz low-cut filter in the unilateral ulnar and tibial nerves were retrospectively investigated to assess whether each MNCS parameter demonstrated demyelinating features that fulfil the European Federation of Neurological Societies/Peripheral Nerve Society electrodiagnostic (EFNS/PNS EDX) criteria for CIDP. RESULTS: Thirteen patients with low compound muscle action potential (CMAP) amplitude in the tibial nerve (0.7 ± 0.7 mV) and prolonged distal CMAP duration in the ulnar nerve satisfied the definite EFNS/PNS EDX criteria for CIDP. Abnormal temporal dispersion and prolongation of distal latency in the tibial nerve were observed in 5 of 13 patients. However, only one of the 13 patients presented with the reduction of motor conduction velocity in each nerve. No patient exhibited conduction block in any nerve. CONCLUSION: Patients with hereditary ATTR amyloidosis occasionally show electrophysiological demyelinating features without conduction block following severe axonal degeneration.

Late-onset Transthyretin (TTR)-familial Amyloid Polyneuropathy (FAP) with a Long Disease Duration from Non-endemic Areas in Japan.

We herein report the case of an 84-year-old woman with transthyretin (TTR) Val30Met-associated familial amyloid polyneuropathy (FAP-ATTR Val30Met), representing a very old case. The patient had muscle weakness and sensory disturbances in her extremities caused by severe peripheral neuropathy. She also had vitreous opacity and orthostatic hypotension, and pyrophosphate scintigraphy showed a myocardial accumulation. Esophagogastroduodenoscopy revealed mucosal amyloid deposits, positive in anti-TTR antibody staining. A TTR gene analysis isolated the Val30Met mutation. More than a few cases of FAP-ATTR develop late, like our own, and their familial histories are often obscure in non-endemic areas, which might make a diagnosis difficult.

Length-dependent truncal Aδ-fiber dysfunction in hereditary transthyretin amyloidosis: An intra-epidermal electrical stimulation study.

OBJECTIVE: To elucidate Aδ-fiber dysfunction at the trunk in patients with hereditary transthyretin (ATTRm) amyloidosis using intra-epidermal electrical stimulation (IES). METHODS: In 16 patients with ATTRm amyloidosis and 18 healthy subjects, sensory thresholds using IES and cooling detection thresholds using the Computer-Aided Sensory Evaluation (CASE IV) system, were assessed to investigate Aδ-fiber functions at the Th10 level of the anterior, lateral, and posterior trunk. Furthermore, evoked potentials (EPs) following electrical stimulation using IES at the anterior and posterior trunk were evaluated. RESULTS: In patients with ATTRm amyloidosis, both IES and CASE IV sensory thresholds tended to be higher at the anterior trunk than at the lateral and posterior trunks. The amplitudes of EPs following electrical stimulation at the anterior trunk were lower than those at the posterior trunk. Aδ-fiber dysfunction at the anterior trunk was conspicuous in patients with more intense polyneuropathy at the limbs. In healthy subjects, there were no differences in both sensory thresholds and EP amplitudes among any examination sites. Sensory thresholds with IES and CASE IV were correlated. CONCLUSIONS: Evaluation using IES demonstrated length-dependent Aδ-fiber dysfunction at the trunk in patients with ATTRm amyloidosis. SIGNIFICANCE: IES may be a useful clinical tool for investigating Aδ-fiber dysfunction at various parts of the body in patients with neuropathy.

Unwanted road to anaemia in transthyretin familial amyloid polyneuropathy may continue irrespective of tafamidis treatment.

Background This retrospective longitudinal study was performed to determine whether tafamidis treatment leads to improvements in commonly used blood data for transthyretin familial amyloid polyneuropathy (TTR-FAP). Methods Commonly used blood data (complete blood count [including a haemogram], total protein, albumin, blood urea nitrogen, creatinine, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, lactate dehydrogenase, γ-glutamyl transpeptidase, total bilirubin [T-Bil], creatine kinase, choline esterase, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, estimated glomerular filtration rate [eGFR], serum amyloid A protein, TTR, haemoglobin A1c, free triiodothyronine [FT3] and free thyroxine [FT4]) were investigated in 33 TTR-FAP patients. These values included longitudinal data at three time points: six months before or after tafamidis treatment and one year after tafamidis treatment. Longitudinal changes in each blood item were examined using a linear mixed model, adjusting for age at starting tafamidis, sex, TTR-FAP stage and value before tafamidis treatment. Results Our results show elevated TTR concentrations after tafamidis treatment. In contrast, haemoglobin, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, mean platelet volume, platelet distribution width, T-Bil, eGFR, FT3 and FT4, gradually decreased through a reference range. There were no characteristic observations in any other items. TTR binds to thyroid hormone; therefore, FT3 and FT4 decreased in inverse proportion to increased TTR concentrations. Conclusion Unfortunately, progression to anaemia may occur regardless of tafamidis treatment. Because anaemia is sometimes present in TTR-FAP, attention should be paid to longitudinal changes in commonly used blood data, irrespective of tafamidis treatment.

Single-centre experience on transthyretin familial amyloid polyneuropathy: case series and literature review.

Familial amyloid polyneuropathy (FAP) is a most often length-dependent axonal neuropathy, often part of a multisystem disorder also affecting other organs, such as cardiac, gastrointestinal, genitourinary, renal, meningeal and eye tissue. It is most frequently the result of a mutation in the TTR gene, most commonly a p.Val50Met mutation. TTR-FAP is a rare autosomal dominant heritable disabling, heterogeneous disease in which early diagnosis is of pivotal importance when attempting treatment. This paper discusses the course of four Belgian FAP patients with different TTR mutations (p.Val48Met; p.Val52Ala; p.Ala59Val; p.Val50Met). We also review the diagnosis and differential diagnosis of TTR-FAP, diagnostic studies, follow-up, its current treatment and those in development, prognosis and the importance of genetic counseling. At first, TTR-FAP is often misdiagnosed as a chronic inflammatory demyelinating polyneuropathy or chronic idiopathic axonal polyneuropathy. Genetic testing is obligatory to confirm the diagnosis of TTR-FAP, except in familial cases. Biopsy samples are an asset in diagnosing TTR-FAP but can be falsely negative. At the moment, tafamidis meglumine is considered as first-line treatment in stage I neurological disease. Patients eligible for liver transplantation should be carefully selected when first-line therapy fails.

Psychopathological Dimensions in Portuguese Subjects with Transthyretin Familial Amyloid Polyneuropathy.

BACKGROUND: Transthyretin familial amyloid polyneuropathy (TTR-FAP) is a fatal, chronic, progressive disease. It is a rare hereditary amyloidosis, which manifests as a sensorimotor neuropathy and autonomic dysfunction. It begins during adulthood. AIMS AND METHODS: Our aim is to evaluate psychopathological dimensions in a population attending a consultation center for TTR-FAP. Two hundred and nine subjects (symptomatic and asymptomatic carriers), 84 men and 127, women participated in the study. Most subjects were married (67.1%) and most of them were still working; 33% were retired from work or on a sick leave. A sociodemographic questionnaire and The Brief Symptom Inventory (BSI) were applied. Statistical analysis was performed (descriptive analysis, Mann-Whitney, Wilcoxon, and Spearman tests). RESULTS: The Global Symptom Index (GSI) was significantly higher in patients (p = 0.001). Considering GSI, 32.7% of total subjects were above the median for general population. When subgroups were evaluated, 25.6% of symptomatic carriers, 26.3% of subjects without established diagnosis, and 39.1% of patients were above median. GSI was significantly higher in patients (p = 0.001). Some BSI dimensions were also significantly higher in the patient group (somatization, depression, anxiety, and psychoticism) when compared with carriers. Women scored higher than men. Sick women scored higher for all dimensions except somatization. Asymptomatic carriers scored statistically higher for phobic anxiety (p = 0.01), interpersonal sensitivity, anxiety, and depression. In patients, most dimensions and GSI (rho = 0.33, p = 0.002) had positive correlations with years of disease. CONCLUSIONS: TTR-FAP patients and carriers are a very vulnerable group for psychological distress and psychopathological problems. Women and patients are at higher risk.

The diagnostic accuracy of Sudoscan in transthyretin familial amyloid polyneuropathy.

OBJECTIVE: Transthyretin familial amyloid polyneuropathy (TTR-FAP) is an axonal sensory-motor and autonomic neuropathy. Reliable quantification of sudomotor function could prove essential in the diagnosis and early treatment management. We aim to assess the diagnostic value of a new sudomotor test (Sudoscan) in TTR-FAP. METHODS: One hundred and thirty-three TTR-FAP Val30Met carriers, divided in asymptomatic and symptomatic stage 1, were compared with 37 healthy controls. We analyzed the right sural sensory nerve action potential (SNAP), the plantar sympathetic skin response (SSR) and the electrochemical skin conductance (ESC) measured by Sudoscan in both hands and feet. RESULTS: All neurophysiological measures were significantly worse in the symptomatic group. However, feet ESC was the only test distinguishing symptomatic patients with autonomic dysfunction from those without autonomic dysfunction, and both groups from asymptomatic subjects and healthy controls. Feet ESC was a significant independent predictor for the presence of symptoms and autonomic failure, after adjusting for demographic characteristics, sural SNAP and SSR amplitudes (p<0.05). Feet ESC showed 76% sensitivity and 85% specificity for detection of dysautonomia. CONCLUSION: Feet ESC is a sensitive test to assess early autonomic dysfunction in TTR-FAP subjects. This investigation should be considered for routine assessment in this population. SIGNIFICANCE: Abnormal feet responses on Sudoscan support early diagnosis in TTR-FAP.

Post hoc analysis of nutritional status in patients with transthyretin familial amyloid polyneuropathy: impact of tafamidis.

INTRODUCTION: Gastrointestinal symptoms are common among patients with transthyretin familial amyloid polyneuropathy (TTR-FAP). This post hoc analysis evaluated the nutritional status of TTR-FAP patients treated with tafamidis while enrolled in clinical trials. METHODS: Nutritional status was measured by the modified body mass index (mBMI = BMI × albumin level). Treatment-related changes in mBMI were reported for 71 Val30Met TTR-FAP patients who completed an 18-month, randomized, double-blind, placebo-controlled trial and who continued into its open-label, 12-month extension. RESULTS: At month 18, mBMI worsened in the placebo group (n = 33) (-33 ± 16 kg/m(2) g/l, P = 0.04 versus baseline) but improved in the tafamidis group (n = 38) (+37 ± 14 kg/m(2) g/l, P = 0.01 versus baseline) such that the effect size between the groups was statistically significant (P = 0.001). By month 30 (completion of the open-label extension), placebo patients with 12 months of tafamidis treatment and tafamidis-treated patients with 30 months of treatment both tended to increase their mBMI (28 ± 19 kg/m(2) g/l and 16 ± 18 kg/m(2) g/l, respectively). Increase in BMI was most pronounced in patients with low BMI at entry into the studies. CONCLUSIONS: mBMI is well suited to monitor disease progression in TTR-FAP patients. The delay in neurological deterioration brought about by tafamidis treatment in clinical trials is associated with improvements in, or maintenance of, mBMI. FUNDING: This study was sponsored by Pfizer Inc., New York, USA.