Long-term treatment of transthyretin familial amyloid polyneuropathy with tafamidis: a clinical and neurophysiological study

Tafamidis is a transthyretin (TTR) stabilizer recently approved to slow the neurologic impairment in TTR familial amyloid polyneuropathy (TTR-FAP). The pivotal studies on Tafamidis reported encouraging results on the short term, in the early onset Val30Met-TTR-FAP patients at an early stage of the neuropathy. However, the effect of the drug in the non-Val30Met patients, at a more advanced stage of the disease and on the long term, is less known. In this study, we report the effect of Tafamidis in 43 TTR-FAP patients with a variety of pathogenic mutations, including 53% of non-Val30Met variants, at different stages of neuropathy followed on the long term. General and neurological assessment was performed in a standardized protocol every 6–12 months along with neurophysiological variables, including testing of small nerve fibres. The mean follow-up under treatment was 2 years with a subset of 26 patients treated for 3 years. Overall, Tafamidis was well tolerated. A significant clinical deterioration of the neuropathy and the patient’s general condition was observed across the 3 years follow-up, although neurophysiological parameters remained stable for the first 2 years. In contrast, patients had a significant increase of BMI under treatment. Deterioration of the neuropathy correlated to an older age at disease onset or treatment initiation and to poor clinical status at baseline. A higher BMI at baseline was associated with a lower progression of the neuropathy. About one-third of the patients who received 3 years of tafamidis had still preserved walking capacity or good clinical condition, suggesting that tafamidis slowed the disease progression in some patients. Overall, our work shows that tafamidis is well tolerated in TTR-FAP but does not prevent the steady progression of the neuropathy on the long term. Age, neurologic status, and general condition at baseline appear to be best predictors of tafamidis efficacy on the neurological function.     

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     

Extended phenotype in the transthyretin Tyr77 familial amyloid polyneuropathy

The transthyretin Tyr77 variant of familial amyloid polyneuropathy (FAP) has been identified in a few North American and European patients, but the full spectrum of its clinical manifestations is still not known. We report a 3-generation family of Jewish-Yemenite origin with Tyr77 FAP presenting with atypical features. The affected individuals had sensorimotor and autonomic neuropathy and cardiomyopathy accompanied by prominent dysphagia, hearing loss and asymptomatic carpal tunnel syndrome. Brain MRI in the proband showed multifocal white matter lesions. These features extend the reported Tyr77 phenotype and support the modifying effect of additional factors on the disease expression.     

Update in the diagnosis and management of transthyretin familial amyloid polyneuropathy

Transthyretin familial amyloid polyneuropathy (TTR-FAP) is a progressive neurodegenerative and systemic genetic disease first identified in Portugal, now reported worldwide. During the past few years our knowledge on the phenotypic presentation of this devastating condition has remarkably expanded including a wide variation in age of onset, different neuropathic patterns and patients presenting with isolated or predominant cardiac involvement. Liver transplantation, the first therapeutic approach, although invasive, has been shown to halt the progression of the neuropathy in young onset patients. Fortunately, several disease-modifying treatments are now available or in clinical development including TTR stabilizers and gene therapy. Their efficacy is higher if administered at the earliest disease stage. Thus, management of TTR-FAP patients is a moving field with need for early diagnosis using new diagnostic tools and new therapeutic options.     

Management of asymptomatic gene carriers of transthyretin familial amyloid polyneuropathy

Transthyretin familial amyloid polyneuropathy (TTR‐FAP) is a rare, severe, and irreversible, adult‐onset, hereditary disorder caused by autosomal‐dominant mutations in the TTR gene that increase the intrinsic propensity of transthyretin protein to misfold and deposit systemically as insoluble amyloid fibrils in nerve tissues, the heart, and other organs. TTR‐FAP is characterized by relentless, progressively debilitating polyneuropathy, and leads to death, on average, within 10 years of symptom onset without treatment. With increased availability of disease‐modifying treatment options for a wider spectrum of patients with TTR‐FAP, timely detection of the disease may offer substantial clinical benefits. This review discusses mutation‐specific predictive genetic testing in first‐degree relatives of index patients diagnosed with TTR‐FAP and the structured clinical follow‐up of asymptomatic gene carriers for prompt diagnosis and early therapeutic intervention before accumulation of substantial damage. Muscle Nerve 54 : 353–360, 2016     

四个TTR-FAP家系的临床特征分析

目的探讨转甲状腺素蛋白相关家族性淀粉样变性周围神经病(TTR-FAP)的临床特征。方法收集空军军医大学第一附属医院神经内科自2017年7月至2019年5月收治的4个TTR-FAP家系(包括20例TTR-FAP患者和2例无症状TTR突变基因携带者)的临床资料,并对其中4例先证者的临床资料进行详细分析。结果20例TTR-FAP患者的发病年龄为30~65岁,均以消化道症状为首发症状,存在不同程度的周围神经损害和体质量明显下降,以及心脏损害9例、体位性低血压9例、性功能障碍5例、排尿异常6例、瞳孔缩小或视物模糊3例,7例经TTR基因检测确诊、3例经腓肠神经病理活检明确,接受二氟尼柳治疗1例、氯苯唑酸治疗2例(病情均进展),死亡12例,存活8例。4例先证者均为男性,发病年龄平均49.3岁;均具有程度不等的感觉运动性周围神经病、自主神经病和心肌病表现;神经电生理检查提示长度依赖性的四肢感觉运动性周围神经病,以轴索损害为著;超声心动图示均有心肌肥厚;3例腓肠神经病理活检发现组织中刚果红染色均呈阳性;全外显子测序显示2例携带TTR基因致病性突变(TTR-E74K、TTR-A140S),1例携带可能致病性突变(TTR-S70R)。2例无症状TTR突变基因携带者仍正常。结论TTR-FAP在临床上表现为周围神经、自主神经持续进行性损害,同时累及多系统,尤其易合并消化道症状、心肌肥厚、体质量明显下降、瞳孔缩小或视物模糊,这些临床特征对该病的诊断有重要提示作用。     

Diagnostic pitfalls in sporadic transthyretin familial amyloid polyneuropathy (TTR-FAP)

Transthyretin familial amyloid polyneuropathies (TTR-FAPs) are autosomal dominant neuropathies of fatal outcome within 10 years after inaugural symptoms. Late diagnosis in patients who present as nonfamilial cases delays adequate management and genetic counseling. Clinical data of the 90 patients who presented as nonfamilial cases of the 300 patients of our cohort of patients with TTR-FAP were reviewed. They were 21 women and 69 men with a mean age at onset of 61 (extremes: 38 to 78 years) and 17 different mutations of the TTR gene including Val30Met (38 cases), Ser77Tyr (16 cases), Ile107Val (15 cases), and Ser77Phe (5 cases). Initial manifestations included mainly limb paresthesias (49 patients) or pain (17 patients). Walking difficulty and weakness (five patients) and cardiac or gastrointestinal manifestations (five patients), were less common at onset. Mean interval to diagnosis was 4 years (range 1 to 10 years); 18 cases were mistaken for chronic inflammatory demyelinating polyneuropathy, which was the most common diagnostic error. At referral a length-dependent sensory loss affected the lower limbs in 2, all four limbs in 20, and four limbs and anterior trunk in 77 patients. All sensations were affected in 60 patients (67%), while small fiber dysfunction predominated in the others. Severe dysautonomia affected 80 patients (90%), with postural hypotension in 52, gastrointestinal dysfunction in 50, impotence in 58 of 69 men, and sphincter disturbance in 31. Twelve patients required a cardiac pacemaker. Nerve biopsy was diagnostic in 54 of 65 patients and salivary gland biopsy in 20 of 30. Decreased nerve conduction velocity, increased CSF protein, negative biopsy findings, and false immunolabeling of amyloid deposits were the main causes of diagnostic errors. We conclude that DNA testing, which is the most reliable test for TTR-FAP, should be performed in patients with a progressive length-dependent small fiber polyneuropathy of unknown origin, especially when associated with autonomic dysfunction.     

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

ObjectiveTransthyretin 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.MethodsThirty-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.ResultsESC (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.ConclusionSudoscan is a fast, non-invasive and easy to perform test, able to distinguish CIDP and TTR-FAP patients with good sensitivity and specificity.SignificanceSudoscan can be helpful in distinguishing between CIDP and TTR-FAP.     

Amyloidogenic transthyretin Val30Met homozygote showing unusually early-onset familial amyloid polyneuropathy

We report an amyloidogenic transthyretin (ATTR) Val30Met homozygote showing extremely early-onset, severe familial amyloid polyneuropathy (FAP). Although homozygotes have been reported to show late-onset and mild clinical manifestations, detailed analyses of the present and previously reported families suggest that homozygotes have a slightly more severe clinical course than heterozygotes. This is the youngest reported patient with ATTR Val30Met FAP, a condition believed to be attributable to homozygosity of this mutation. The clinical severity is consistent with TTR protein instability.     

Clinical features of familial amyloid polyneuropathy carrying transthyretin mutations in four Chinese kindreds

Transthyretin‐related familial amyloid polyneuropathy (TTR‐FAP) is a rare hereditary disorder, characterized by a length‐dependent polyneuropathy and dysfunction of various organs. Wide phenotypic heterogeneity makes early diagnosis difficult. In this study, we reviewed the clinical and electrophysiological features of four unrelated Chinese families with genetically confirmed TTR‐FAP. Sequence analysis of TTR gene revealed the presence of four different mutations: Thr49Ala(p.Thr69Ala), Leu55Arg(p.Leu75Arg), Tyr116Ser(p.Tyr136Ser), and Ala36Pro(p.Ala56Pro) from six affected patients and two asymptomatic individuals. Two mutations, Thr49Ala(p.Thr69Ala) and Tyr116Ser(p.Tyr136 Ser), were detected in Chinese FAP patients for the first time. All affected patients manifested a progressive sensorimotor polyneuropathy starting in the lower limbs. The majority of the examined patients displayed cardiomyopathy and vitreous opacities. To avoid misdiagnosis, clinicians should consider screening for TTR variants in patients presenting with progressive polyneuropathy of undetermined origins.     

A sporadic case of late-onset familial amyloid polyneuropathy type I (transthyretin Met 30-associated familial amyloid polyneuropathy) inborn habitant of Ehime prefecture]

We reported a 62-year-old man of late-onset familial amyloid polyneuropathy type I(transthyretin Met 30-associated familial amyloid polyneuropathy) from Ehime Prefecture. There was no family history related to endemic Japanese foci (Nagano and Kumamoto foci). He demonstrated paraesthesia in the legs and mild autonomic symptoms at the age of 52. These symptoms gradually developed. Analysis of the transthyretin gene from his leucocytes demonstrated he had Met 30 transthyretin mutation. Therefore, he was diagnosed with late-onset familial amyloid polyneuropathy type I(FAP 1). In some families, asymptomatic carriers with the mutant transthyretin gene were diagnosed. In early stage, this patient's polyneuropathy and autonomic nervous system dysfunction were less serious than those of FAP 1 patients from endemic Japanese foci. These symptoms of this patient was slowly progressive. He hoped liver transplantation (brain death or living-related) treatment if possible. Now he became 68-year-old and bed-ridden.     

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.     

肝移植治疗家族性淀粉样变多发性神经病

家族性淀粉样变多发性神经病(familial amyloid polyneuropathy,FAP)为一罕见型常染色体显性遗传疾病,与转甲蛋白(transthyretin,TTR)基因的80多个位点突变相关。临床上以进行性的周围神经、自主神经病变及不同程度的内脏器官淀粉样蛋白质沉积为特征。FAP的病理基础即是转甲     

Electrophysiological features of late-onset transthyretin Met30 familial amyloid polyneuropathy unrelated to endemic foci

BACKGROUND : Through the development of gene diagnostic techniques, late-onset transthyretin Met30-associated familial amyloid polyneuropathy (FAP TTR Met30) has been shown to be more prevalent than is generally believed. OBJECTIVE : To examine the electrophysiological features of late-onset FAP TTR Met30 unrelated to endemic foci. METHODS : Nerve conduction findings in 44 cases with an onset of more than 50 years of age in a non-endemic area were assessed and compared with findings from 21 earlier-onset cases related to endemic foci. RESULTS : The extent of the reduction of the compound muscle action potential and, especially, the sensory nerve action potential was more profound in the late-onset group even when the decline of these indices with aging in normal control subjects was taken into account. The feature of predominant lower-limb involvement seemed to be more conspicuous in the late-onset group. Electrophysiological indices tended to be aggravated as the duration of neuropathic symptoms increased in the early-onset group, while most of these indices in the lateonset group did not show this correlation. A slowing of conduction velocity and a prolongation of distal latency, which suggests demyelination, were conspicuous in some patients. Pathologically, a predominant loss of small-fibers was not conspicuous in sural nerve biopsy specimens from late-onset patients. Large myelinated fiber density showed a negative correlation with the disease duration in early-onset cases, but not in late-onset cases. CONCLUSIONS : Electrophysiological differences between late- and early-onset cases were present, probably reflecting the different underlying pathogenic mechanisms of neuropathy. The demyelinating feature does not exclude the possibility of this disease.