transthyretin familial amyloid polyneuropathy ( ttrfap ) is an autosomaldominant , adultonset disorder associated with over 100 different mutations in the transthyretin ( ttr ) gene that cause transthyretin protein to deposit as amyloid in peripheral and autonomic nerves , heart , gastrointestinal ( gi ) tract , kidneys , eyes , and connective tissue of the transversal carpal ligament ( ando et al . , 2013 ; rowczenio et al . , 2014 ; sekijima , 2015 ) .
this results in progressive organ dysfunction and death within an average of 10 years ( ando et al . , 2013 ) .
ttrfap is a highly heterogeneous disease associated with a wide range of clinical manifestations that may present in varying degrees and combinations ( ando et al . , 2013 ; sekijima , 2015 ) .
the disease can be difficult to recognize due to its variable clinical presentation and nonspecific symptoms .
the age of onset ranges from the second to ninth decade of life ( ando et al . , 2013 
 ) , and incomplete penetrance of clinical disease can lead to sporadic cases without known affected relatives .
accurate diagnosis of ttrfap is often delayed for years ( plantbordeneuve et al . , 2007 ; koike et al . , 2011 ;
an accurate diagnosis is important to permit effective disease management , as tissue damage is largely irreversible , and available treatment options are most beneficial in early disease stages ( coelho et al . , 2013 ; plantbordeneuve , 2014 ; ericzon et al . , 2015
a particular challenge in making a diagnosis is that clinical manifestations are not necessarily uniform among carriers of the same ttr mutation and can vary even within the same family ( ando et al . , 2013 
 ) .
the clinical phenotype is also influenced by genetic , epigenetic , or environmental factors other than the ttr mutation ( see table 1 ) .
gi , gastrointestinal ; ttrfap , transthyretin familial amyloid polyneuropathy ; sd , standard deviation .
urinary retention might be underdiagnosed as patients are usually not aware or cognisant of symptoms .
lengthdependent peripheral sensorymotor neuropathy is a hallmark feature of ttrfap . in classical earlyonset ( < 50 years of age )
val30met ttrfap ( andrade , 1952 
 ) , distal small myelinated and unmyelinated nerve fibers associated with pain and temperature sensation become damaged first , which may manifest as paresthesia , dysesthesia , allodynia , hyperalgesia , or spontaneous pain in the feet .
axonal degeneration then progresses relentlessly in a distal to proximal pattern reaching upper limbs usually 4 to 5 years after first symptoms . within a few years
, larger myelinated sensory and motor nerve fibers become affected and impairment of light touch , vibration , and position sensation , and motor deficit appear in the distal lower limbs .
lateonset cases are characterized by relative preservation of unmyelinated nerve fibers and conspicuous presence of axonal sprouting ( koike et al . , 2004 
 ) .
these characteristics are responsible for impaired superficial and deep sensation , severe neuropathic pain , early distal motor involvement , and relatively mild autonomic symptoms ( conceio and de carvalho , 2007 ; koike et al . ,
the lengthdependent pattern of symmetric sensorymotor and autonomic polyneuropathy in ttrfap is not unique , and similar neurologic impairments can be observed in many conditions , all of which can mislead clinical diagnosis .
the most common neuropathic misdiagnosis for sporadic ttrfap is chronic inflammatory demyelinating polyneuropathy ( cidp ) ( plantbordeneuve , 2014 
 ) .
for instance , 20% of 90 french patients without a family history of ttrfap ( plantbordeneuve et al . , 2007 
 ) and
53% of 15 japanese patients with sporadic v30 m ttrfap ( koike et al . , 2011 
 )
although cidp is generally characterized by a demyelinating sensorymotor neuropathy , once extensive axonal lengthdependent damage is present , electrophysiological characteristics of ttrfap can resemble those of cidp due to secondary demyelination .
furthermore , protein levels in cerebrospinal fluid can be elevated in patients with ttrfap , albeit less markedly than in cidp . in some cases ,
given the frequent misdiagnosis , there should be a high suspicion index for ttrfap in patients diagnosed with cidp that do not respond to immunomodulatory treatment .
there have been numerous cases where ttrrelated amyloidosis was initially misdiagnosed as amyloid lightchain ( al ) amyloidosis ( cowan et al . , 2011 ; briani et al . ,
misdiagnosis can be due to occurrence of monoclonal gammopathy in elderly patients or false immunolabeling of amyloid deposits , leading to inappropriate , potentially harmful chemotherapeutic treatment .
ttrfap is unlikely to be mistaken for other forms of hereditary amyloid neuropathy caused by mutation of the apolipoprotein ai , gelsolin , or 2microglobulin genes .
however , although very rare and less rapidly progressive , hereditary neuropathy due to truncation mutations of the prion protein can closely mimic ttrfap ( mead and reilly , 2015 
 ) and should be considered in the differential diagnosis .
consequently , it is important to obtain a complete clinical history with details of symptoms of systemic disease and a complete and detailed family history ( ando et al . , 2013 ; plantbordeneuve , 2014 
 ) .
the occurrence of progressive peripheral sensorymotor polyneuropathy and at least one of the following is suggestive of ttrfap : family history of neuropathy , early autonomic dysfunction , cardiac involvement , diarrhea , constipation , alternating episodes of constipation and diarrhea , inexplicable weight loss , carpal tunnel syndrome , renal impairment , or vitreous opacity ( fig .
symptom clusters that may warn of a diagnosis of transthyretin familial amyloid polyneuropathy ( ttrfap ) . of these combinations ,
peripheral neuropathy with early autonomic signs , such as erectile dysfunction or gi symptoms , and peripheral neuropathy with cardiac manifestations are the most common and important combinations in sporadic patients .
rapid disease progression ( dohrn et al . , 2013 
 ) and failure to respond to immunomodulatory treatment are additional signs .
the clusters of clinical symptoms mentioned above should raise suspicion of ttrfap , particularly if there is a positive family history . in patients with suspected ttrfap
, the entire coding region of the ttr gene , that is all four exons , should be sequenced .
tissue biopsy analysis and neurologic , cardiac , autonomic , and ophthalmologic evaluation can lend further credence to the correct diagnosis .
 abstracttransthyretin familial amyloid polyneuropathy ( ttrfap ) is a rare , progressive , lifethreatening , hereditary disorder caused by mutations in the transthyretin gene and characterized by extracellular deposition of transthyretinderived amyloid fibrils in peripheral and autonomic nerves , heart , and other organs . 
 ttrfap is frequently diagnosed late because the disease is difficult to recognize due to phenotypic heterogeneity . 
 based on published literature and expert opinion , symptom clusters suggesting ttrfap are reviewed , and practical guidance to facilitate earlier diagnosis is provided . 
 ttrfap should be suspected if progressive peripheral sensorymotor neuropathy is observed in combination with one or more of the following : family history of a neuropathy , autonomic dysfunction , cardiac hypertrophy , gastrointestinal problems , inexplicable weight loss , carpal tunnel syndrome , renal impairment , or ocular involvement . 
 if ttrfap is suspected , transthyretin genotyping , confirmation of amyloid in tissue biopsy , large and smallfiber assessment by nerve conduction studies and autonomic system evaluations , and cardiac testing should be performed . 
Introduction
Clinical Features of TTRFAP
Common Diagnostic Pitfalls
Redflag Symptom Combinations That May Warn of a Diagnosis of TTRFAP
Core Diagnostic Tests to Identify TTRFAP