Diagnostic delay in patients with sporadic hereditary transthyretin-mediated amyloidosis.

BACKGROUND: Hereditary transthyretin-mediated amyloidosis (ATTRv amyloidosis) is a rare progressively incapacitating condition with a wide range of genotype/phenotype presentations. It is frequently diagnosed late in its course, particularly in sporadic cases. OBJECTIVES: Analysing predictors of diagnostic delay in this subpopulation should be, therefore, a priority. METHODS: 109 apparently sporadic ATTRv amyloidosis patients followed in a reference centre in Hospital de Santa Maria (ULS Santa Maria-CAML), in Lisbon, were studied. Time from symptom onset to diagnosis, age, sex, municipality of origin and initial symptoms were obtained. Diagnostic delay was compared between different decades with a Kruskal-Wallis test, and its predictors were evaluated in a univariate model followed by a binary logistic regression analysis to calculate the adjusted odds ratio. RESULTS: The median diagnostic delay was 1262 days. There was a non-significant difference in diagnostic delay between the 80 s, 90 s, 2000s and 2010s decades. There was a non-significant trend for a longer diagnostic delay in woman and in patients having no neurologic symptoms at onset. CONCLUSION: There is an important diagnostic delay in sporadic cases of ATTRv amyloidosis. Awareness should be spread among clinicians regarding the various manifestations of this disease, stressing the importance of family history and epidemiological data.

Quantification of muscle involvement in familial amyloid polyneuropathy using MRI.

BACKGROUND AND PURPOSE: Transthyretin familial amyloid polyneuropathy (TTR-FAP) is a rare genetic disease with autosomal-dominant inheritance. In this study, we aimed to quantify fatty infiltration (fat fraction [FF]) and magnetization transfer ratio (MTR) in individual muscles of patients with symptomatic and asymptomatic TTR-FAP using magnetic resonance imaging. Secondarily, we aimed to assess correlations with clinical and electrophysiological variables. METHODS: A total of 39 patients with a confirmed mutation in the TTR gene (25 symptomatic and 14 asymptomatic) and 14 healthy volunteers were included. A total of 16 muscles were manually delineated in the nondominant lower limb from T1-weighted anatomical images. The corresponding masks were propagated on the MTR and FF maps. Detailed neurological and electrophysiological examinations were conducted in each group. RESULTS: The MTR was decreased (42.6 AU; p = 0.001) and FF was elevated (14%; p = 0.003) in the lower limbs of the symptomatic group, with preferential posterior and lateral involvement. In the asymptomatic group, elevated FF was quantified in the gastrocnemius lateralis muscle (11%; p = 0.021). FF was significantly correlated with disease duration (r = 0.49, p = 0.015), neuropathy impairment score for the lower limb (r = 0.42, p = 0.041), Overall Neuropathy Limitations Scale score (r = 0.49, p = 0.013), polyneuropathy disability score (r = 0.57, p = 0.03) and the sum of compound muscle action potential (r = 0.52, p = 0.009). MTR was strongly correlated to FF (r = 0.78, p < 0.0001), and a few muscles with an FF within the normal range had a reduced MTR. CONCLUSION: These observations suggest that FF and MTR could be interesting biomarkers in TTR-FAP. In asymptomatic patients, FF in the gastrocnemius lateralis muscle could be a good indicator of the transition from an asymptomatic to a symptomatic form of the disease. MTR could be an early biomarker of muscle alterations.

Bilateral Progressive Optic Neuropathy in a Patient with Familial Amyloid Polyneuropathy: Amyloid Deposits in the Optic Nerve Head?

Familial amyloid polyneuropathy is a rare autosomal dominant hereditary disease. Optic nerve involvement is frequently observed secondary to uncontrolled glaucoma but, rarely, an ischaemic optic neuropathy can occur. In this case report we describe a patient who presented with bilateral progressive visual loss and constriction of his visual fields. Fundus examination showed intense paleness of both optic discs with elevated, poorly defined margins that seemed to be infiltrated. Fundus autofluorescence and enhanced-depth imaging optical coherence tomography ruled out the presence of optic disc drusen. Orbital magnetic resonance imaging ruled out any sign of orbital compression, inflammation or infiltration of the optic nerve. The mechanism of small vessel amyloid infiltration and a possible vessel compression by amyloid in the optic nerve head is discussed.

3-T MR neurography of lumbo-sacral plexus in hereditary transthyretin-related amyloidosis with polyneuropathy.

OBJECTIVES: Our aim was to evaluate the ability of magnetic resonance neurography (MRN) of the lumbo-sacral plexus (LSP) to distinguish patients with hereditary transthyretin-related amyloidosis with polyneuropathy (ATTRv-PN) from asymptomatic variant carriers (AVC) and healthy controls and to assess its prognostic value. METHODS: Three-Tesla MRN was performed in 25 consecutive ATTRv-PN patients, 18 AVC, and 10 controls including T2-w DIXON and DWI MR sequences. Two blinded readers independently assessed LSP root diameter and intraneural signal on the MRN images of each subject. MRN findings were compared between groups and correlated with clinical impairment scored on the Neuropathy Impairment Score (NIS) and the modified Polyneuropathy Disability score (mPND). RESULTS: The agreement between readers on MRN images was excellent (Cohen's kappa = 0.82). LSP root enlargement was significantly more frequent in ATTRv-PN patients compared to AVC (ratio = 4.38, p = 0.038). Increased LSP root intraneural signal on T2-w images was significantly more frequent in ATTRv-PN patients compared to AVC (ratio = 3.4, p = 0.016). In contrast, there were no MRN abnormalities in controls. In ATTRv-PN patients, LSP root enlargement was associated with higher mPND scores (p = 0.03) and increased intraneural signal on T2-w images was associated with significantly higher NIS and mPND scores (p = 0.004 and 0.02, respectively). CONCLUSIONS: MRN of the LSP can help differentiate ATTRv-PN patients from AVC. LSP root enlargement and increased intraneural signal are significantly associated with clinical impairment, suggesting potential implications for patient care. KEY POINTS: • ATTRv-PN patients showed abnormal LSP changes on MRN. • MRN of the LSP can help to differentiate ATTRv-PN patients from AVC and healthy controls. • LSP root enlargement and increased intraneural signal were significantly associated with clinical impairment in ATTRv-PN patients.

A Study of Familial Amyloid Polyneuropathy Induced by the TTR Val30Leu Mutation in China.

INTRODUCTION: Familial amyloid polyneuropathy is currently prevalent worldwide as the transthyretin (TTR) Val30Met mutation, and there are other types of mutations. The purpose of this study was to understand the clinical manifestations, electrophysiological characteristics, and outcomes of hormone-related therapy in patients with the TTR Val30Leu mutation in China. METHODS: Clinical data were collected from 9 members of a family with the TTR Val30Leu mutation in China, and blood samples of 7 members of the family were sequenced. The electrophysiological examinations of 4 of them were collected and analysed. RESULTS: A total of 7 people had the TTR gene c.148G>T missense mutation and the TTR protein Val30Leu mutation in this family, and the positive members all had similar symptoms, such as limb paraesthesia and gastrointestinal symptoms. In addition, electrophysiological examination showed abnormal nerve conduction velocity in all 4 patients. CONCLUSIONS: The clinical manifestations of this mutation involve mainly limb sensory or motor disorders or gastrointestinal symptoms or both, and the electrophysiological examination shows neurogenic damage.

A low amyloidogenic E61K transthyretin mutation may cause familial amyloid polyneuropathy.

Patients with transthyretin (TTR)-type familial amyloid polyneuropathy (FAP) typically exhibit sensory dominant polyneuropathy and autonomic neuropathy. However, the molecular pathogenesis of the neuropathy remains unclear. In this study, we characterize the features of FAP TTR the substitution of lysine for glutamic acid at position 61 (E61K). This FAP was late-onset, with sensory dominant polyneuropathy, autonomic neuropathy, and cardiac amyloidosis. Interestingly, no amyloid deposits were found in the endoneurium of the four nerve specimens examined. Therefore, we examined the amyloidogenic properties of E61K TTR in vitro. Recombinant wild-type TTR, the substitution of methionine for valine at position 30 (V30M) TTR, and E61K TTR proteins were incubated at 37°C for 72 hr, and amyloid fibril formation was assessed using the thioflavin-T binding assay. Amyloid fibril formation by E61K TTR was less than that by V30M TTR, and similar to that by wild-type TTR. E61K TTR did not have an inhibitory effect on neurite outgrowth from adult rat dorsal root ganglion (DRG) neurons, but V30M TTR did. Furthermore, we studied the sural nerve of our patient by terminal deoxynucleotidyl transferase dUTP nick end labeling and electron microscopy. A number of apoptotic cells were observed in the endoneurium of the nerve by transferase dUTP nick end labeling. Chromatin condensation was confirmed in the nucleus of non-myelinating Schwann cells by electron microscopy. These findings suggest that E61K TTR is low amyloidogenic, in vitro and in vivo. However, TTR aggregates and amyloid fibrils in the DRG may cause sensory impairments in FAP because the DRG has no blood-nerve barrier. Moreover, Schwann cell apoptosis may contribute to the neurodegeneration.

Targeting transthyretin - Mechanism-based treatment approaches and future perspectives in hereditary amyloidosis.

The liver-derived, circulating transport protein transthyretin (TTR) is the cause of systemic hereditary (ATTRv) and wild-type (ATTRwt) amyloidosis. TTR stabilization and knockdown are approved therapies to mitigate the otherwise lethal disease course. To date, the variety in phenotypic penetrance is not fully understood. This systematic review summarizes the current literature on TTR pathophysiology with its therapeutic implications. Tetramer dissociation is the rate-limiting step of amyloidogenesis. Besides destabilizing TTR mutations, other genetic (RBP4, APCS, AR, ATX2, C1q, C3) and external (extracellular matrix, Schwann cell interaction) factors influence the type of onset and organ tropism. The approved small molecule tafamidis stabilizes the tetramer and significantly decelerates the clinical course. By sequence-specific mRNA knockdown, the approved small interfering RNA (siRNA) patisiran and antisense oligonucleotide (ASO) inotersen both significantly reduce plasma TTR levels and improve neuropathy and quality of life compared to placebo. With enhanced hepatic targeting capabilities, GalNac-conjugated siRNA and ASOs have recently entered phase III clinical trials. Bivalent TTR stabilizers occupy both binding groves in vitro, but have not been tested in trials so far. Tolcapone is another stabilizer with the potential to cross the blood-brain barrier, but its half-life is short and liver failure a potential side effect. Amyloid-directed antibodies and substances like doxycycline aim at reducing the amyloid load, however, none of the yet developed antibodies has successfully passed clinical trials. ATTR-amyloidosis has become a model disease for pathophysiology-based treatment. Further understanding of disease mechanisms will help to overcome the remaining limitations, including application burden, side effects, and blood-brain barrier permeability.

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.

Between responsibility and desire: Accounts of reproductive decisions from those at risk for or affected by late-onset neurological diseases.

This paper explores ways in which genetic risk foregrounds forms of responsibility while dealing with reproduction. We analyzed individual and family semi-structured interviews (n = 35) with people at-risk for or affected by transthyretin-related familial amyloid polyneuropathy (TTR-FAP) and Machado-Joseph disease (MJD), which are late-onset neurological diseases. Although generally considered as rare diseases, some areas in Portugal present the world's highest frequency for MJD and TTR-FAP. Thematic analysis of the data revealed that participants drew on various - sometimes ambivalent and competing - understandings of their genetic risk and their wish to have children. Some participants perceived the avoidance of genetic risk to be responsible behavior, while, for others, responsibility entailed accepting risks because they prioritized values such as parenthood, family relationships and the value of life, above any question of genetic disease. Some participants shared accounts that were fraught with ambivalence, repentance and guilt, especially when children were born before participants knew of their own or their partner's risk. Participants' accounts also showed they make continued efforts to see themselves as responsible persons and to appear responsible in the eyes of others. We discuss findings in the context of participants' negotiation between genetic risk and their sense of responsibility toward themselves and others; we conclude that "genetic responsibility" is present not only in accounts of those who chose not to have children but also in those who make an informed decision to have at-risk children.

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.

Transthyretin-related familial amyloid polyneuropathy (ATTR-FAP) in Poland - genetic and clinical presentation.

BACKGROUND: Transthyretin-related familial amyloid polyneuropathy (ATTR-FAP) is a rare, progressive, hereditary, highly disabling multisystem disorder. ATTR-FAP phenotypes differ according to the type of TTR mutation, geographic region and other as yet unidentified factors. The aim of this study was to establish the clinical and genetic characteristics of Polish patients. METHODS AND PATIENTS: Clinical data and necessary examinations were collected from patients diagnosed with ATTR-FAP at the Department of Neurology of Medical University of Warsaw between 1970 and 2019. RESULTS: 16 patients from eight unrelated families with five different TTR mutations were identified. The family with Val71Ala TTR mutation presented with early onset severe progressive polyneuropathy, with marked visual symptoms in a few patients. The next family with Ile73Val TTR mutation developed symptoms in middle age, and presented with mixed neuropathic and cardiologic phenotype. Four unrelated families were found to have the Phe33Leu TTR mutation with mixed neuropathic and cardiologic phenotype and late onset of symptoms. Other TTR mutations identified were: Val30Met and Asp38Val, both with late onset sensory, motor and autonomic neuropathy. CONCLUSION: Polish ATTR-FAP cases presented with heterogeneity typical for non-endemic areas. Phe33Leu TTR mutation was the most common, found in four unrelated families.

Inflammatory profiling of patients with familial amyloid polyneuropathy.

BACKGROUND: Familial amyloid polyneuropathy (FAP) or ATTRv (amyloid TTR variant) amyloidosis is a fatal hereditary disease characterized by the deposition of amyloid fibrils composed of transthyretin (TTR). The current diagnosis of ATTRv relies on genetic identification of TTR mutations and on Congo Red-positive amyloid deposits, which are absent in most ATTRv patients that are asymptomatic or early symptomatic, supporting the need for novel biomarkers to identify patients in earlier disease phases allowing disease control. METHODS: In an effort to search for new markers for ATTRv, our group searched for nine inflammation markers in ATTRv serum from a cohort of 28 Brazilian ATTRv patients. RESULTS: We found that the levels of six markers were increased (TNF-α, IL-1ß, IL-8, IL-33, IFN-ß and IL-10), one had decreased levels (IL-12) and two of them were unchanged (IL-6 and cortisol). Interestingly, asymptomatic patients already presented high levels of IL-33, IL-1ß and IL-10, suggesting that inflammation may take place before fibril deposition. CONCLUSIONS: Our findings shed light on a new, previously unidentified aspect of ATTRv, which might help define new criteria for disease management, as well as provide additional understanding of ATTRv aggressiveness.

Characteristics and natural history of autonomic involvement in hereditary ATTR amyloidosis: a systematic review.

BACKGROUND: Autonomic dysfunction is a hallmark feature of hereditary ATTR amyloidosis. The aim of this study was to summarize the characteristics and natural history of autonomic dysfunction in patients with hereditary ATTR amyloidosis. METHODS: A systematic review of the natural history and clinical trials of patients with ATTR amyloidosis was performed. Alternative surrogate markers of autonomic function were analyzed to understand the prevalence and outcome of autonomic dysfunction. RESULTS: Patients with early-onset disease displayed autonomic dysfunction more distinctively than those with late-onset disease. The nutritional status and some autonomic items in the quality-of-life questionnaires were used to assess the indirect progression of autonomic dysfunction in most studies. Gastrointestinal symptoms and orthostatic hypotension were resent earlier than urogenital complications. Once symptoms were present, their evolution was equivalent to the progression of the motor and sensory neuropathy impairment. CONCLUSION: The development of autonomic dysfunction impacts morbidity, disease progression, and mortality in patients with hereditary ATTR amyloidosis.

Transthyretin Amyloid Neuropathy: The Schwann Cell Hypothesis.

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.

Sensory nerve degeneration in a mouse model mimicking early manifestations of familial amyloid polyneuropathy due to transthyretin Ala97Ser.

AIMS: Sensory nerve degeneration and consequent abnormal sensations are the earliest and most prevalent manifestations of familial amyloid polyneuropathy (FAP) due to amyloidogenic transthyretin (TTR). FAP is a relentlessly progressive degenerative disease of the peripheral nervous system. However, there is a lack of mouse models to replicate the early neuropathic manifestations of FAP. METHODS: We established human TTR knock-in mice by replacing one allele of the mouse Ttr locus with human wild-type TTR (hTTRwt ) or human TTR with the A97S mutation (hTTRA97S ). Given the late onset of neuropathic manifestations in A97S-FAP, we investigated nerve pathology, physiology, and behavioural tests in these mice at two age points: the adult group (8 - 56 weeks) and the ageing group (> 104 weeks). RESULTS: In the adult group, nerve profiles, neurophysiology and behaviour were similar between hTTRwt and hTTRA97S mice. By contrast, ageing hTTRA97S mice showed small fibre neuropathy with decreased intraepidermal nerve fibre density and behavioural signs of mechanical allodynia. Furthermore, significant reductions in sural nerve myelinated nerve fibre density and sensory nerve action potential amplitudes in these mice indicated degeneration of large sensory fibres. The unaffected motor nerve physiology replicated the early symptoms of FAP patients, that is, sensory nerves were more vulnerable to mutant TTR than motor nerves. CONCLUSIONS: These results demonstrate that the hTTRA97S mouse model develops sensory nerve pathology and corresponding physiology mimicking A97S-FAP and provides a platform to develop new therapies for the early stage of A97S-FAP.

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.

Clinical outcomes after preimplantation genetic diagnosis of patients with Corino de Andrade disease (familial amyloid polyneuropathy).

The aim of this study was to determine whether patients with transthyretin-related hereditary amyloidosis (V30M), after transplantation or under tafamidis treatment, have normal gamete reproductive capacity. A retrospective analysis was carried out of all preimplantation genetic diagnosis (PGD) cycles performed in patients with the V30M mutation. The groups analysed were: total cases with V30M, female cases with V30M and male cases with V30M. Detailed demographic, stimulation, embryological, clinical and newborn outcomes were evaluated. Comparisons revealed that patients have a high likelihood of achieving a live birth per PGD treatment cycle (48%). This is the first large report on patients with the V30M mutation treated with PGD. The high rate of live birth obtained should represent a strong stimulus for patients to use PGD as it proved to be effective and safe. As a neurodegenerative disease that leads to death, it is of maximum importance that it could be eradicated using PGD in order to definitively avoid the transmission of the disease.

Hereditary amyloidosis related to transthyretin V30M: disease progression in treated and untreated patients.

BACKGROUND AND PURPOSE: Hereditary amyloidosis related to transthyretin V30M (hATTR V30M) is a progressive length-dependent sensorimotor axonal neuropathy. We aimed to compare the disease progression of treated [liver transplantation (LT) or tafamidis] versus untreated patients with hATTR V30M. METHODS: A total of 81 patients with hATTR V30M were included: 27 untreated, 25 treated with LT and 29 undergoing tafamidis treatment. Neuropathy was assessed at baseline, 12, 24 and 36 months after study entry. We evaluated disease stage, modified polyneuropathy disability (mPND) score and a composite neurophysiological score comprised of sensory and motor conduction parameters. The effect of treatment on disease progression was analysed using linear mixed-effects modelling. RESULTS: At baseline, patients from the untreated group were older (P < 0.01) and those in the LT group had longer disease duration than those in the tafamidis group (P < 0.05). Gender, mPND and motor scores at study entry were equal in the three groups; however, the untreated group had lower sensory scores compared with the tafamidis group (P < 0.01). During the 3-year follow-up period, progression to stage II of the disease was seen only in the untreated group. The progression on mPND, sensory and motor scores was significantly higher in the untreated patients. When treated groups were compared, the LT group had lower rates of composite neurophysiological score progression. However, the sensory score outcome was similar between tafamidis responders and LT patients. CONCLUSION: Both LT and tafamidis therapy modified the natural history of hATTR V30M by reducing neuropathy progression.

Tafamidis delays neurological progression comparably across Val30Met and non-Val30Met genotypes in transthyretin familial amyloid polyneuropathy.

BACKGROUND AND PURPOSE: To better characterize the effects of tafamidis in non-Val30Met patients with transthyretin familial amyloid polyneuropathy, this post hoc analysis compared the neurological results from a 12-month, open-label study of non-Val30Met versus Val30Met patients at month 12 from the 18-month, double-blind, placebo-controlled registration study. A baseline covariate adjusted analysis was used to control for differences in baseline neurological severity. METHODS: Neurological function was assessed using the Neuropathy Impairment Score - Lower Limbs (NIS-LL) in three cohorts: Val30Met tafamidis (n = 64), Val30Met placebo (n = 61) and non-Val30Met tafamidis (n = 21). The change in NIS-LL from baseline to month 12 for Val30Met and non-Val30Met tafamidis-treated patients was compared with the change from baseline at month 12 for Val30Met placebo-treated patients using a mixed-effects model for repeated measures (MMRM). RESULTS: The baseline adjusted mean (standard error) change in NIS-LL values at month 12 was similar for Val30Met [1.60 (0.78)] and non-Val30Met [1.62 (1.43)] tafamidis-treated patients and less than that observed in the Val30Met placebo-treated group [4.72 (0.77); P = 0.0055 for Val30Met and P = 0.0592 for non-Val30Met]. Based on the MMRM, the magnitude of change in both tafamidis-treated cohorts was similar across the range of observed baseline NIS-LL values, and was consistently less than that observed in the Val30Met placebo-treated group at month 12. CONCLUSIONS: This baseline-adjusted analysis demonstrated that tafamidis treatment delayed neurological progression comparably in Val30Met and non-Val30Met patients across a range of baseline NIS-LL values. Neurological progression in these two genotype groups may be more similar than previously considered.