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the institutional review board at the university of california , irvine , approved this retrospective study .
medical records were reviewed from patients suspected of having amyloid polyneuropathy seen in the neuromuscular clinic at the university of california , irvine , between 2010 and 2015 .
both patients in this study provided informed consent . the diagnosis , suspected by clinical presentation and electrodiagnostic studies , was confirmed by genetic testing , with a mutation reported in the ttr gene .
the institutional review board at the university of california , irvine , approved this retrospective study .
medical records were reviewed from patients suspected of having amyloid polyneuropathy seen in the neuromuscular clinic at the university of california , irvine , between 2010 and 2015 .
both patients in this study provided informed consent . the diagnosis , suspected by clinical presentation and electrodiagnostic studies , was confirmed by genetic testing , with a mutation reported in the ttr gene .
a 75-year - old woman developed progressive sensory loss affecting her legs and hands accompanied by mild diffuse weakness with severe asymmetric bilateral foot drops over a period of 2 years .
additional findings on examination included tongue atrophy and fasciculations , sensory loss to all modalities in legs and hands , areflexia , and sensory ataxia .
electrodiagnostic studies showed a severe axonal sensorimotor polyneuropathy with ongoing denervation changes ( fibrillation potentials ) seen on needle examination of distal leg muscles .
sural nerve biopsy showed severe axonal loss ; however , it was negative for amyloid ( congo red staining )
. given the concern for autonomic dysfunction with new symptoms of dizziness in the setting of a severe neuropathy , ttr genetic testing was performed and revealed a heterozygous mutation in exon 4 ( c.379a > g resulting in p.i127v substitution , legacy nomenclature p.i107v ) .
a 60-year - old man noted rapidly progressive painless weakness and sensory loss affecting both legs and arms requiring a wheelchair for mobility and accompanied by dysarthria and dysphagia over a 3-year period .
his examination findings included dysarthria , tongue atrophy ( figure , a ) with fasciculations , bilateral foot drops with severe distal - greater - than - proximal weakness , profound sensory loss , areflexia , and a wide - based ataxic gait .
electrodiagnostic studies revealed a severe axonal sensorimotor polyneuropathy with diffuse active denervation changes ( fibrillation potentials ) on needle examination of the arms and legs .
his brother died at 61 years of age , with a reported diagnosis of amyotrophic lateral sclerosis ( als ) .
given the patient 's severe neuropathy and possible family history , ttr genetic testing was performed and revealed a heterozygous mutation in exon 2 ( c.148g > a resulting in p.v50 m substitution , legacy nomenclature p.v30 m ) .
a lip biopsy showed ttr - positive deposits in the minor salivary glands ( figure , b ) .
( a ) marked tongue atrophy  note the furrowing of the lateral aspects of the tongue .
( b ) a photomicrograph of a minor salivary gland biopsy showing an immunoperoxidase staining for transthyretin ( ttr ) ( dark brown ) . diffuse deposition of ttr - positive amyloid is seen in these glands .
the patient did not meet inclusion criteria for the ongoing antisense oligonucleotide trial in familial amyloid polyneuropathy secondary to markedly abnormal neuropathy impairment score .
a 75-year - old woman developed progressive sensory loss affecting her legs and hands accompanied by mild diffuse weakness with severe asymmetric bilateral foot drops over a period of 2 years .
additional findings on examination included tongue atrophy and fasciculations , sensory loss to all modalities in legs and hands , areflexia , and sensory ataxia .
electrodiagnostic studies showed a severe axonal sensorimotor polyneuropathy with ongoing denervation changes ( fibrillation potentials ) seen on needle examination of distal leg muscles .
sural nerve biopsy showed severe axonal loss ; however , it was negative for amyloid ( congo red staining )
. given the concern for autonomic dysfunction with new symptoms of dizziness in the setting of a severe neuropathy , ttr genetic testing was performed and revealed a heterozygous mutation in exon 4 ( c.379a > g resulting in p.i127v substitution , legacy nomenclature p.i107v ) .
a 60-year - old man noted rapidly progressive painless weakness and sensory loss affecting both legs and arms requiring a wheelchair for mobility and accompanied by dysarthria and dysphagia over a 3-year period .
his examination findings included dysarthria , tongue atrophy ( figure , a ) with fasciculations , bilateral foot drops with severe distal - greater - than - proximal weakness , profound sensory loss , areflexia , and a wide - based ataxic gait .
electrodiagnostic studies revealed a severe axonal sensorimotor polyneuropathy with diffuse active denervation changes ( fibrillation potentials ) on needle examination of the arms and legs .
his brother died at 61 years of age , with a reported diagnosis of amyotrophic lateral sclerosis ( als ) .
given the patient 's severe neuropathy and possible family history , ttr genetic testing was performed and revealed a heterozygous mutation in exon 2 ( c.148g > a resulting in p.v50 m substitution , legacy nomenclature p.v30 m ) .
a lip biopsy showed ttr - positive deposits in the minor salivary glands ( figure , b ) .
( a ) marked tongue atrophy  note the furrowing of the lateral aspects of the tongue .
( b ) a photomicrograph of a minor salivary gland biopsy showing an immunoperoxidase staining for transthyretin ( ttr ) ( dark brown ) . diffuse deposition of ttr - positive amyloid is seen in these glands .
the patient did not meet inclusion criteria for the ongoing antisense oligonucleotide trial in familial amyloid polyneuropathy secondary to markedly abnormal neuropathy impairment score .
ttr - fap is well characterized as a progressive length - dependent sensorimotor polyneuropathy with autonomic and multiorgan systemic involvement ; however , clinical heterogeneity ranges from isolated carpal tunnel syndrome to sensory neuropathy , painful neuropathy , pure dysautonomia , chronic inflammatory demyelinating polyradiculoneuropathy , and even a motor - predominant neuropathy .
several case reports of ttr - fap describe a motor neuropathy with bulbar palsies ( tongue atrophy and fasciculations ) resembling motor neuron disease and have led to concerns of a misdiagnosis of als .
the majority of these rare motor - predominant neuropathy cases associated with the ttr mutation were initially suspected of having motor neuron disease , especially given the affiliated cranial nerve involvement of dysarthria , dysphagia , tongue atrophy , and fasciculations .
most of these cases were characterized by lower motor neuron features of progressive motor weakness greater than sensory involvement , atrophy , fasciculations , and areflexia with or without associated dysautonomia symptoms .
the focal manifestation of macroglossia has more commonly been described in systemic primary amyloidosis secondary to amyloid accumulation ; however , tongue atrophy and fasciculations are underrecognized features in patients with ttr - fap .
we report 2 additional patients with tongue atrophy and fasciculations who have genetically confirmed ttr - fap . in patients with severe rapidly progressive polyneuropathy and bulbar weakness ,
ttr - fap thus joins a list of other rare genetic metabolic or neurodegenerative disorders that present with features of atypical als and should be considered in the differential diagnosis of sporadic or familial als .
unusual clinical characteristics that may indicate a diagnosis other than als may include severe polyneuropathy , dysautonomia , very slow progression , prominent lower motor neuron features ( in the absence of upper motor neuron findings ) , severe dementia , and/or a constellation of multisystemic features in a neurologic patient .
this list of atypical conditions that may mimic als includes adult - onset polyglucosan body disease ( dementia , sensory neuropathy , and motor neuronopathy ) , late - onset hexosaminidase a deficiency ( presenting as spinal muscular atrophy phenotype or als with upper and lower motor neuron findings ; prominent cerebellar and neuropsychiatric findings help differentiate it from typical als ) , multisystem proteinopathy with mutations in the valosin - containing protein gene ( can be associated with als , inclusion body myopathy , paget disease , frontotemporal dementia , and even parkinson disease , with phenotypic variability often in the same kindred ) , and allgrove syndrome , with mutations in the aaa ( aladin ) gene ( presenting with a sensorimotor neuropathy , autonomic disorder , and , most prominently , early - onset alacrimia , achalasia , and adrenal insufficiency [ aaa]the trio of aaa symptoms ) .
careful investigation of symptoms or signs that point to an alternate diagnosis , such as the ones discussed above , should be done in all patients when considering a diagnosis of als with atypical clinical features .
. conceived of the project and designed the study ; collected and analyzed the data ; and wrote and edited the manuscript .
dr . goyal has received clinical research support from alnylam and isis pharmaceuticals for ongoing clinical experimental trials in fap .
dr . mozaffar has received clinical research support from alnylam , isis pharmaceuticals , alexion , amicus , biomarin , csl , genzyme , gsk , novartis , ultragenyx , and nih ; has served on the medical and scientific advisory boards for the myositis association , genzyme corporation , idera pharmaceuticals , and ultragenyx ; has received travel reimbursement for advisory board meetings for genzyme corporation , biomarin , and amicus ; has been a consultant for amicus , biomarin , genzyme , sarepta , and ultragenyx ; and has served on the speakers ' bureau for genzyme corporation .
objective : macroglossia is a well - known feature of amyloidosis ; however , tongue atrophy and fasciculations are rarely seen and can lead to the misdiagnosis of amyotrophic lateral sclerosis ( als).methods : we identified 2 unrelated patients with atypical features of tongue atrophy and fasciculations in the setting of a severe neuropathy.results:both patients were confirmed to have transthyretin - related familial amyloid polyneuropathy ( ttr - fap ) by genetic testing.conclusions:ttr-fap should be considered as a possible mimicker of als when tongue atrophy and fasciculations are seen in the setting of a severely progressive polyneuropathy . 
 other atypical mimickers of als include polyglucosan body disease , hexosaminidase a deficiency , multisystem proteinopathy , and allgrove syndrome .