Clinical variant of familial amyloid polyneuropathy

Hereditary amyloidosis with early and prominent peripheral nerve involvement is often designated familial amyloid polyneuropathy (FAP). The abnormality usually lies in the transthyretin (TTR) gene. We describe a patient with a tyr77 TTR gene mutation who presented with sensorimotor polyneuropathy but no other systemic symptoms of amyloidosis. This is one of a few documented cases of the tyr77 mutation in North America. The clinical and electrophysiologic features of this unusual cause of sensorimotor polyneuropathy are discussed.     

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.     

Charcot-Marie-Tooth disease (CMT): distinctive phenotypic and genotypic features in CMT type 2

Charcot-Marie-Tooth disease (CMT), or hereditary motor and sensory neuropathy (HMSN), includes two main subtypes of CMT1/HMSN I (demyelinating), and CMT2/HMSN II (axonal). Further heterogeneity has been demonstrated by genetic molecular studies, with at least four responsible genes for CMT1. As for CMT2, a mutation in the neurofilament-light (NF-L) gene has been identified in a single family, and other CMT2 loci have been mapped. We propose a clinical classification of the CMT2 phenotypes, and review the features of the identified CMT2 genotypes. The following main subtypes of CMT2 are considered in the phenotype classification: classical CMT2, the variants of CMT2 showing atypical features that may represent either variance in the classical CMT2 phenotype or separate entities; CMT2 plus, i.e. complex forms with involvement of additional neural structures. The recognized CMT2 genotypes include: CMT2A (mapped to chromosome 1p35-36); CMT2B (3q13-22); CMT2C (with vocal cord paresis); CMT2D (7p14); CMT2E, related to a mutation in the NF-L gene on chromosome 8p21; proximal CMT2, or HMSN P (3q13.1); CMT2 with MPZ mutations; autosomal recessive CMT2 (1q21.2-q21.3); agenesis of the corpus callosum with sensorimotor neuronopathy (15q13-q15); CMT2 X-linked with deafness and mental retardation (Xq24-q26). The identified genotypes may correspond to previously described clinical subtypes of CMT2. In particular, classical CMT2 presents in association with NF-L gene mutation, in the only CMT2 family with known gene mutation, and in CMT2A patients. However, the features of classical CMT2 have been paradoxically reported also in families with MPZ mutation, and conversely several CMT2 families are not linked to the known CMT2 loci. Further cloning of the CMT2 genes will ultimately shed light on the pathogenic mechanism(s) implicated in the process of axonal degeneration, shared by the different CMT2 genotypes.     

Transthyretin familial amyloid polyneuropathy (TTR‐FAP) in Mallorca: a comparison between late‐ and early‐onset disease

The age of onset (AO) of hereditary ATTR amyloidosis (hATTR) is known to vary between populations, with differing characteristics reported according to AO in endemic/non‐endemic foci. This was a retrospective study of patients with early AO (<50 years) and late AO (≥50 years) hATTR at our center in Mallorca. Data were collected on patient demographics, clinical disease manifestation, and physical symptoms. A total of 95 patients were analyzed, with mean follow‐up of 9 years from diagnosis. The early AO group included 53 patients (33 male) and the late AO group included 42 patients (21 male). Neurologic involvement was the most common initial symptom, although it was significantly more frequent in the late AO vs. early AO group (p = 0.015). Autonomic involvement was observed in 26% of patients in the early AO group, but was rarely observed in the late AO group (5%). During follow up, cardiologic symptoms, renal involvement, and ophthalmologic symptoms were significantly more common in the late AO group (p < 0.05). This retrospective study demonstrates the variation in disease presentation and progression according to AO of hATTR at our Mallorcan center.     

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.     

Expansion of the phenotypic spectrum of X-linked Charcot-Marie-Tooth (CMT) disease

Charcot-Marie-Tooth (CMT) disease is the most common hereditary peripheral neuropathy. X-linked Charcot-Marie-Tooth disease in the GJB1 gene is known as CMTX1. We report a 14 years-old young man with walked unstably, bilateral strephenopodia, severe alopecia and paroxysmal bilateral upper limbs tremor without obvious muscle atrophy. Diagnostic whole-exome sequencing revealed a hemizygote missense mutation c.278 T > A in exon 2 of the GJB1 gene, with lysine at position 93 of the mature protein (p.M93K). This is the first CMT case with alopecia areata reported in the world.     

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.     

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。     

Reliability of the CMT neuropathy score (second version) in Charcot-Marie-Tooth disease

The Charcot-Marie-Tooth neuropathy score (CMTNS) is a reliable and valid composite score comprising symptoms, signs, and neurophysiological tests, which has been used in natural history studies of CMT1A and CMT1X and as an outcome measure in treatment trials of CMT1A. Following an international workshop on outcome measures in Charcot-Marie-Tooth disease (CMT), the CMTNS was modified to attempt to reduce floor and ceiling effects and to standardize patient assessment, aiming to improve its sensitivity for detecting change over time and the effect of an intervention. After agreeing on the modifications made to the CMTNS (CMTNS2), three examiners evaluated 16 patients to determine inter-rater reliability; one examiner evaluated 18 patients twice within 8 weeks to determine intra-rater reliability. Three examiners evaluated 63 patients using the CMTNS and the CMTNS2 to determine how the modifications altered scoring. For inter- and intra-rater reliability, intra-class correlation coefficients (ICCs) were ≥0.96 for the CMT symptom score and the CMT examination score. There were small but significant differences in some of the individual components of the CMTNS compared with the CMTNS2, mainly in the components that had been modified the most. A longitudinal study is in progress to determine whether the CMTNS2 is more sensitive than the CMTNS for detecting change over time.     

The diagnosis and management of familial amyloid polyneuropathy

INTRODUCTION: Familial amyloid polyneuropathy designates a group of dominantly inherited neuropathies, with extracellular deposition of amyloid substance in various tissues. BACKGROUND: The 3 main precursor proteins encountered in these disorders are transthyretin, apolipoprotein A1 or gelsolin. Among them, transthyretin neuropathies are by far the most frequent type with a severe sensori-motor and autonomic neuropathy as the hallmark of the disease, most often associated with cardiac manifestations. First described in Portugal, the affection was subsequently reported across the world, although Portugal, Japan and Sweden are the 3 main areas of prevalence. In the past years, an increasing number of mutations have been identified in the TTR gene, along with a larger clinical spectrum than initially thought. Variable age of onset and penetrance are also largely reported with unclear phenotypic-genotypic correlations. Indeed, the contribution of the molecular genetics is important to ensure the diagnosis at an early stage, but also for predictive diagnosis, in the setting of genetic counselling. PERSPECTIVES: Over the last 15 years, liver transplantation (LT) has enabled improved prognosis of this devastating condition. Future prospects: at present, such procedure should be performed in Val30Met patients, as early as possible in the course of the disease. Experience with such procedure in patients with other TTR variants remains scarce. Other therapeutic strategies are awaited. CONCLUSION: This review summarizes the recent data on the diagnosis and management of patients and families affected with TTR amyloid neuropathy.     

Type I familial amyloid polyneuropathy and pontine haemorrhage

A Portuguese female, aged 47 years, who had emigrated to Spain, was admitted to the hospital in 1991 for pontine haematoma. The patient, four siblings and her father were affected by a peripheral neuropathy, indicating autosomal dominant inheritance. The patient presented in the 2nd decade with sensory and motor neuropathy beginning in the lower extremities. Alternating constipation and diarrhoea, and urinary incontinence became uncontrollable. She had to be colostomised, and, eventually, confined to a wheelchair from the age of 43. Neurological examination showed bilateral facial involvement, and severe signs of sensory and motor peripheral neuropathy, and later right hemiplegia. There were abnormalities of atrial rhythm and left bundle branch block. Computerised axial tomography and magnetic resonance images demonstrated left-sided pontine haemorrhage. Nerve conduction studies revealed severe diminution of motor conduction velocity and absence or reduction of amplitude of sensory and motor action potentials. Inanition and a respiratory infection led to her death. Clinical diagnosis was type I familial amyloid polyneuropathy (FAP). Postmortem examination demonstrated amyloid deposits in peripheral nerves, including spinal roots and cranial nerves, leptomeninges, thyroid, breasts, heart, adrenal glands, kidneys, intestines, pancreas, and meningeal and some pontine vascular structures. Advanced pontine haematoma was verified. Cerebral haemorrhage usually occurs with cerebrovascular amyloidosis, but exceptionally with FAP. A minority of patients presenting with CNS haemorrhage showed arteriovenous malformation or embolism [Da Silva Horta and Dias Coelho (1960) Arch de Vecchi Anal Patol Med Clin 31=163–172]. However, amyloid deposition in some small pontine vessels could have played a role in the pathogenesis of haemorrhage in the present case.     

A new diagnostic procedure to detect unknown transthyretin (TTR) mutations in familial amyloidotic polyneuropathy (FAP)

Two patients with amyloidosis caused by transthyretin (TTR) were investigated by immunohistopathologic, mass spectrometric, and molecular genetic methods. After confirming the immunoreactivity of TTR in the amyloid deposits using anti-TTR polyclonal antibody, a new method: centrifugal concentration and electrospray ionization mass spectrometry (ESI-MS) was employed to detect the variant TTR in the serum. Only 50 microl of the serum and 30 microl of the anti-TTR antibody were needed for the analysis. After incubation with the antibody, the samples were passed through a 1000 kDa cut off centrifugal concentrator to retain the antibody, thereafter, the filtrate was analyzed by ESI-MS. Several forms of normal and variant TTR were detected in the serum samples: unconjugated TTR, cysteine and cysteine-glycine conjugated TTR. In the patients, a variant form of TTR was detected with a 26.0 Da higher molecular weight than that of normal TTR. Single-strand conformation polymorphism (SSCP) and direct sequence analysis confirmed the presence of a one-base substitution situated at the codon 50 from AGT (Ser) to ATT (Ile) in both patients, that corresponded to the increased molecular weight of 26.0. The present diagnostic procedure demonstrates the usefulness of both ESI-MS and SSCP to screen for TTR related amyloidosis rapidly. Moreover, the DNA samples obtained from the band showing abnormal electrophoretic migration pattern in SSCP, facilitate the direct sequence analysis to detect the unknown mutation, and the observed shift in molecular weight of the variant TTR in ESI-MS confirms the base substitution.     

Penetrance estimation of TTR familial amyloid polyneuropathy (type I) in Brazilian families

Background and purpose:  Familial amyloid polyneuropathy (FAP) type I is a severe autosomal dominant inherited neuropathy associated with mutations in the transthyretin (TTR) gene. Significant phenotypic variability is seen amongst families with distinct geographic origin, especially regarding penetrance and age of onset. The aim of this study was to estimate the penetrance of FAP in Brazilian families.
Methods:  Twenty-two distinct families were ascertained through genetically confirmed index cases and included in this study. Genealogical and clinical data were obtained from a total of 623 individuals, including 126 affected by FAP. In 15 families, TTR genotyping was performed in all available relatives ( n  = 86), after informed written consent. Seven families did not consent for genetic testing, but agreed to provide clinical and genealogical data. Penetrance was estimated using a previously described method based on survival analysis and corrected for ascertainment bias.
Results:  Mean age of onset in our sample was 34.5 years, with a significant earlier onset in males (31.1 vs. 35.9, P  < 0.0001). The penetrance of FAP in our sample was estimated as 83% (95% CI: 66–99) after 60 years.
Conclusion:  Our results provide new information on FAP in Brazilian patients and may be helpful in the genetic counseling of this population.     

家族性淀粉样变性周围神经病的发病机制研究进展

家族性淀粉样变性周围神经病(familial amyloid polyneuropathy,FAP)是一种具有遗传性的淀粉样变性类疾病,以常染色体显性遗传为特征,并具有广泛的种族分布.疾病最初表现为周围神经病及自主神经功能障碍,但随着病情的逐渐进展而导致越来越多的脏器受累.在欧洲,1952年葡萄牙人就首次报道了该病,到1994年为止,共有489个葡萄牙家系的约1233名患者被确诊为FAP.在20世界60、70年代,瑞典和日本分别出现了FAP家系,并证实他们的祖先具有葡萄牙血统[1].     

Phenotypic expression of familial amyloid polyneuropathy in Brazil

Familial amyloid polyneuropathy (FAP) is an inherited amyloidosis mainly associated with transthyretin Val30Met variant. Clinical heterogeneity has been reported in different populations with FAP and Va130Met variant. In order to characterize FAP expression in Brazilians and to compare its features to those reported in other cohorts, 44 Brazilian patients (27 females, median age 36 [23-53] years) with FAP and the Val30Met variant were investigated. Approximately 40% of their family members, with the exception, of parents and siblings, had FAP. Most of the patients had symptoms of peripheral neuropathy at onset. Median age at onset was 32 [20-44] years. Earlier onset was observed in males (27 [20-43] years in males vs. 33 [20-44] years in females, P = 0.02) and in patients whose parents had FAP (31 [20-44] years vs. 40 [37-43] years in patients, respectively with and without affected parents, P = 0.03). Phenotypic expression of FAP in Brazil is similar to the one reported in Portugal, characterized by high disease penetrance, early onset, particularly in males and in subjects with affected parents, and major symptoms of peripheral neuropathy. These data highlight the influence of common genetic factors, shared by both groups of patients, in disease expression.     

转甲蛋白相关家族性淀粉样周围神经病的临床、病理与遗传学研究

目的 探讨转甲蛋白相关家族性淀粉样周围神经病(TTR-FAP)患者的临床、电生理、组织病理和遗传学表现.方法 对北京协和医院2006-2014年确诊的13个家系(先证者)和散发TTR-FAP病例进行临床观察、分期、系统评估和随访.对其中12例进行了周围神经和(或)肌肉活组织检查(活检),主要采用腓浅神经与腓骨短肌联合活检.同时采用转甲蛋白免疫组织化学染色和转甲蛋白基因检测.结果 (1)临床表现:13例先证者和散发病例,男性11例,女性2例,发病年龄17 ～53岁,平均37.7岁.5例以周围神经病起病;4例以晕厥和(或)短暂脑缺血发作样症状起病;4例以腹泻起病.从发病到确诊的平均时间为2.96年.全部患者均有感觉和运动性周围神经病和自主神经功能障碍.临床分期1期4例,2期5例,3期4例.(2)神经肌肉活检病理:周围神经病理改变为慢性活动性轴索性损害,肌肉病理改变以神经源性损害为主,刚果红和转甲蛋白免疫组织化学染色阳性,提示转甲蛋白阳性物质淀粉样物质在神经与肌肉中沉积.(3)基因检测发现10种点突变,其中E54Q点突变未见报道.(4)诊疗与转归:对全部患者予维生素营养神经治疗,3例近期予二氟尼柳治疗,5例于发病后3～6年死亡.结论 TTR-FAP呈现基因型和临床表型的多样性,经典的V30M型在我国可能不是优势类型.本组病例以早发型为主,部分患者进展迅速,可能与特定的基因突变类型有关.神经肌肉联合活检加转甲蛋白免疫组织化学染色可提供TTR-FAP组织学确诊证据.     

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.