hereditary amyloidosis represents a clinically and genetically heterogeneous group of autosomal dominant inherited diseases characterized by the deposit of insoluble variants of physiological proteins in the extracellular matrix . mutated transthyretin ( ttr ) , formerly called prealbumin and encoded by a gene on chromosome 18 , is the most frequent protein implicated , whereas apolipoprotein a1 , lysozyme , fibrinogen , gelsolin , amyloid- and cystatin c are much more uncommon . ttr is a tetrameric serum protein involved in the transport of serum thyroxine and retinol - binding protein synthesized in the liver and , minimally , in the choroid plexus . its variation enables the dissociation of tetrameric ttr , which increases the concentration of aberrant amyloidogenic monomers . ttr amyloidosis is characterized by slowly progressive peripheral sensorimotor and autonomic neuropathy [ 1 , 3 ] as well as cardiomyopathy , nephropathy , vitreous opacities , and central nervous system involvement . portugal and japan are the countries with the largest endemic foci . in this study , we report a 63-year - old man who carries a missense mutation in the ttr gene and presented with rapidly progressive axonal motor neuropathy , clinically resembling a motor neuron disease , with subclinical signs of sensory involvement . the patient first came to our attention when he was 63 years old . he presented with increasing weakness of the lower limbs , muscle fatigue , and dysphagia , which began at the age of 59 years . his neurological symptoms worsened over the years , resulting in a greater difficulty in climbing the stairs and standing up from a chair . he had a positive cardiological history that included supraventricular arrhythmia ( treated with ablation of the arrythmogenic focus ) and atrial fibrillation ( which resolved after pharmacological therapy ) . in addition , he had a right eye cataract , paget 's disease , chronic renal failure due to glomerulonephritis , gastroesophageal reflux , and hepatic steatosis . at 45 and 55 years of age , the patient underwent surgical decompressions for bilateral carpal tunnel syndrome with a secondary lesion of the right median nerve . his family history was positive for cardiomyopathy , type ii diabetes mellitus , hypertension , cancer , and parkinson 's disease . the patient 's father died at 63 years of age due to renal failure , and his mother died at 69 years of age due to ovarian neoplasm . he had 1 brother and 1 sister , both of whom had bilateral carpal tunnel syndrome and myopia ; the brother also had cataracts and the sister underwent surgery for uterine neoplasm . an electromyogram ( emg ) detected an axonal motor neuropathy with minimal sensory impairment ; the amplitude of the sensory nerve action potential was decreased ( 4 v right ; 6 v left ) . a muscle biopsy , performed on the quadriceps femoris , showed a neurogenic pattern characterized by high size variability , with several atrophic fibers and fiber type ii grouping . connective tissue increase , anti - gm1 igm antibodies were mildly increased ( 1/640 ) . in the following months , the patient exhibited a severe and rapid progression of the motor impairment of the 4 limbs , characterized by muscle atrophy and fasciculation , without comparable clinical defect of the sensory component . since the subclinical sensory impairment , only detectable with electrophysiology , was interpreted as incidental finding , the patient was diagnosed with probable amyotrophic lateral sclerosis ( als ) , although his clinical presentation was more suggestive of progressive muscular atrophy ; he was therefore referred to our motor neuron disease center . the patient underwent an extensive clinical assessment , comprehensive of family and personal history data recording , complete neurological examination , and muscle strength evaluation using the medical research council and als functional rating scale . our neurological examination revealed bulbar signs such as tongue atrophy and fasciculation , nasal voice , and dysarthria . the patient presented with some difficulty in digital skills , hand weakness with diffuse fasciculation , and atrophy of the right arm . he had bilateral mild proximal muscle weakness in the lower limbs , with a particular atrophy in the distal regions ( right > left ) . a sensory deficit was observed only in the first 3 fingers of the right hand . the emg was repeated and showed a pattern characterized by electroneurographical findings compatible with motor - sensory neuropathic involvement . at nerve conduction study , the tibial posterior nerve showed a reduced compound muscle action potential amplitude ( 0.9 and 0.5 mv ) and a reduced nerve conduction velocity ( ncv ; 36.5 and 36.4 m / s ) . the sensitive ncv of the sural nerve was reduced bilaterally ( 36.2 and 33.3 m / s ) , as were the ncv and sensitive action potential amplitude of the ulnar ( 46.6 m / s ) and radial ( 50 m / s ) nerves . the concentric electric needle examination demonstrated neurogenic signs predominantly at the lower limbs , with fibrillation potentials and motor unit action potentials characterized by prolonged amplitude and duration . since the patient had a sporadic occupational exposure to polychlorinated biphenyls , he was also examined by a specialist in occupational medicine who excluded any possible link between the patient 's polyneuropathy and work . the superoxide dismutase 1 gene was screened as the first gene in our familial als assessment protocol , and the valosin - containing protein gene was analyzed because of the comorbid paget 's disease . a more detailed medical history investigation revealed the presence of dysautonomia presenting as erectile dysfunction that was not previously reported . for this reason , no additional autonomic tests were performed , but specific tests to examine the sensory and dysautonomic involvement will be considered during follow - up . the remote and familial history and the findings of dysautonomia and mild sensory impairment associated with systemic aspects ( above - mentioned cardiac , ocular and renal features ) suggested revising the patient 's diagnosis , and amyloid etiopathogenesis was considered . we decided to perform a ttr gene molecular analysis and detected the presence of a heterozygous missense mutation ( p.tyr78phe ; c.293a > t according to ensembl genome browser i d otthumt00000254948 ) ( fig . samples from the patient 's parents were not available for further investigation because both were deceased and other siblings were not available for analysis . the pathogenic role of this mutation was confirmed through a sural nerve biopsy analysis , which showed a mild axonal neuropathic pattern characteristic of amyloidosis and demonstrated a reduced myelinization that was more evident in semi - thin sections , with conserved bimodal distribution . endoneurial connective tissue was increased , blood vessels were normal , and cellular infiltrates were absent . the quantitative analysis showed a fiber density of 1,475 nerve fibers / mm ( normal value according to the age : 4,800  1,000 ) . a teasing technique showed a normal aspect in 49% of the fibers , total demyelinization in 41% , and axonal degeneration in 6% ; 2% presented with segmental demyelinization or remyelinization , respectively ( fig . the disease was confirmed through specific staining with congo red , which revealed strongly positive deposits in several capillary walls that appeared as apple - green birefringence when examined under polarized light . given that liver transplantation is still the only recognized therapy for ttr polyneuropathy , this possibility was proposed to our patient , who is now waiting for transplantation . mutations in the ttr gene are among the most frequent causes of hereditary autosomal dominant amyloidosis and are mainly responsible for familial amyloid polyneuropathy ( fap ) , which is characterized by predominant sensorimotor and autonomic involvement due to endoneurial and polyvisceral extracellular deposition of amyloid substance . , we describe the case of a patient with predominant motor involvement , leading to a diagnostic hypothesis of motor neuron disease . the major clinical features of this patient were distal limb paralysis , atrophy , fasciculations , dysphagia , and dysarthria . the sensory and autonomic deficits were minimal and were only identified after accurate electroneurographic study and complete clinical data collection . these aspects , in association with the patient 's past medical history of carpal tunnel syndrome as well as the presence of some systemic defects such as renal impairment , cardiac fibrillation , and cataracts , led to the suspicion of amyloidosis . molecular analysis revealed the presence of the heterozygous missense mutation p.tyr78phe in the ttr gene . the pathogenicity of this mutation and the link between amyloid deposition and polyneuropathy were confirmed histologically by the sural nerve biopsy , which demonstrated mild peripheral axonal neuron sufferance with positive birefringent deposits at congo red staining . the amyloidogenic properties of the tyr78phe mutation of the ttr gene have also been demonstrated by redondo et al , who showed that the substitution of residue 78 led to a changed tetrameric structure that might represent an early intermediate in the fibrillogenesis pathway . although the p.tyr78phe mutation is rare , it has been described once before in a 78-year - old french man of italian origin who was affected with late - onset peripheral neuropathy in the lower limbs , bilateral carpal tunnel , and skin amyloidosis . more than 100 pathogenic mutations leading to misfolding and formation of amyloid deposits have been detected in the ttr gene . these mutations are mainly single nucleotide substitutions with an autosomal pattern of transmission but variable penetrance . among them , the substitution of a methionine at codon 30 ( p.val30met ) was the first to be described   and so far remains the most frequent , especially in portugal , north sweden , and japan . other variants can present a wide clinical interfamilial variability , probably due to epigenetic and environmental factors . usually , fap is progressing faster than in our patient , and even if there are no studies to date correlating ttr mutations and survival , the very rare mutation in our patient could be related to a disease form with longer evolution . the peculiar aspect in this case was the unusual manifestation of polyneuropathy with a predominant motor involvement and only minimal and late - onset sensory and dysautonomic signs . sensory and autonomic involvement can be subtly but definitely present in amyloidosis , and new investigation tools may help to test sensitive and dysautonomic symptoms in ttr mutation polyneuropathy and to identify the amyloid pathologic substrate . the value of standard quantitative autonomic and sensation tests in detecting , characterizing , and quantifying the severity of ttr amyloid polyneuropathy has recently been assessed . in addition , the quantitative assessment of cutaneous nerve fibers can be employed as an indicator of the severity of neuropathy . identifying a specific causative amyloid protein from nerves and other tissues is often difficult but important in diagnosis and treatment . the possibility of distinguishing the specific type of amyloidosis from nerve biopsies combining laser microdissection and mass spectrometric - based proteomic analysis has also been recently described . some of these methods are still experimental and were not applied in our case , but they may be considered for the assessment and follow - up of ttr patients . the above - mentioned atypical manifestation of fap has only been described in a single case by quattrini et al . . because of this finding , amyloid polyneuropathy should be considered as an alternative diagnosis of motor neuron disease , especially in the presence of systemic symptoms , such as carpal tunnel syndrome and cataract , renal , heart , or skin involvement . the clinical phenotypic heterogeneity of ttr mutations and the predominant motor or sensory / dysautonomic pattern can be explained by the complex multifactorial mechanisms that regulate amyloid fibrillogenesis in fap , such as the intrinsic conformation of the ttr fibril protein , its concentration , the structural effects of the ttr mutation , microenvironments of the lysosome , proteolytic processing , amyloid cofactors , and tissue - specific determinants . we underscore that the negative results from the periumbilical fat and muscle biopsies does not exclude the diagnosis . in fact , in our patient the periumbilical fat biopsy did not reveal amyloid deposition , and the muscle biopsy must be completed with specific methods , such as congo red staining , which are not routinely used . the recognition of amyloid etiologies in patients affected with predominant motor polyneuropathy with few sensory signs is fundamental . in fact , the molecular definition of this disease can help in genetic counseling , because the mutation is inherited in an autosomal dominant manner . furthermore , the early diagnosis of amyloid neuropathy allows the timely starting of potential therapies , such as liver transplantation .
transthyretin ( ttr ) amyloidosis , the most frequent form of hereditary amyloidosis , is caused by dominant mutations in the ttr gene . 
 more than 100 mutations have been identified . 
 clinical manifestations of ttr amyloidosis are usually induced by extracellular amyloid deposition in several organs . 
 the major neurological manifestation is motor - sensory neuropathy associated with dysautonomic impairment . here , we describe a 63-year - old man who came to our institution due to a suspected motor neuron disease . during a 4-year follow - up period 
 , he underwent extensive clinical examination , electromyographic studies , sural nerve biopsy and ttr gene analysis by direct sequencing . despite the predominant motor involvement , 
 the detailed clinical examination also showed some mild sensory and dysautonomic signs . 
 in addition , his clinical and family history included multiorgan disorders , such as carpal tunnel syndrome , as well as conditions with cardiac , renal , eye , and hepatic involvement . 
 the sural nerve biopsy disclosed amyloid deposition , and the sequence analysis of the ttr gene detected a heterozygous tyr78phe substitution . 
 the ttr gene variant found in our patient had only been described once so far , in a french man of italian origin presenting with late - onset peripheral neuropathy and bilateral carpal tunnel syndrome . 
 the predominant motor involvement presented by our patient is an uncommon occurrence and demonstrates the clinical heterogeneity of ttr amyloidosis .