Additional Investigation After the Biopsy Diagnosis

The patient underwent genetic testing, which showed a pathological mutation c.238A > G (p.Thr80Ala) in the transthyretin (TTR) gene. This mutation has been reported in sporadic cases of hereditary amyloidosis in non-endemic areas [1–3].

Final Diagnosis

Familial Amyloid Polyneuropathy Caused by a TTR Gene Mutation

Patient Follow-up

The diagnosis of familial amyloid polyneuropathy caused by the Thr80Ala TTR mutation and the new therapies for the disease were discussed with the patient. The patient was started on Diflunisal, a TTR stabilizer, and Inotersen, a TTR silencer and a transthyretin-directed antisense oligonucleotide drug. His nausea and vomiting were partially controlled by antiemetics. Orthostatic dizziness improved after taking pyridostigmine bromide. Neuropathic pain was largely controlled by maximizing the dose of pregabalin. The patient was sent for genetic counseling.

Discussion

Peripheral neuropathy commonly occurs in both hereditary and acquired amyloidosis . Immunoglobulin light chain (AL) amyloidosis is the most common form of acquired amyloidosis, whereas transthyretin (TTR) amyloidosis is the most common form of hereditary amyloidosis. When neuropathy is the primary feature of amyloidosis related to a TTR mutation, it is often referred to as neuropathic hATTR amyloidosis , or familial amyloid polyneuropathy, which is caused by one of over 140 mutations in the transthyretin gene. It is familial and transmitted in an autosomal dominant manner, although sporadic cases exist.

Transthyretin is a plasma transport protein for retinol binding protein and thyroid hormone . It is produced in the liver, with small amounts produced in the choroid plexus and retinal pigment epithelium of the eye [4–6]. When mutated, TTR misfolds and aggregates as insoluble amyloid fibrils that deposit in various organs and leads to dysfunction and even failure of affected organs. Amyloid can deposit in any part of the peripheral nervous system including nerves, nerve roots, autonomic and spinal ganglia and muscle [7, 8]. Patients often present with sensorimotor polyneuropathy, carpal tunnel syndrome and autonomic dysfunction. Small myelinated and unmyelinated axons are more affected than large myelinated axons. Depending on which organ the fibrils deposit, patients can also have cardiomyopathy, reduced gastrointestinal motility, renal insufficiency, and vitreous opacities [9].

The most common TTR mutation is a substitution of Methionine for Valine at position 30, the ATTRVal30Met mutation (or V30M mutation), whereas in the United States, the most common mutation is the substitution of isoleucine for valine at position 122, or the V122I mutation which affects 3% of African Americans [10]. The V122I mutation is commonly associated with cardiomyopathy, although neuropathy can be seen in 10–38% of patients [10, 11]. Penetrance varies by mutation type, and having a genetic mutation does not necessarily mean that patients will develop the disease [12]. Clinical presentation can vary widely worldwide. In endemic regions of Japan, northern Portugal, Sweden, and Cyprus, patients present in the third or fourth decade classically with pain and temperature abnormalities in the feet. Later, light touch and proprioception are impaired with proximal progression of symptoms up the legs and eventual weakness that can be debilitating. Autonomic dysfunction can manifest with orthostatic hypotension, dry eyes, dry mouth, gastroparesis with fluctuating constipation and diarrhea, urinary retention, and erectile dysfunction in men. Significant adrenergic, cardiovagal or sudomotor autonomic dysfunction can be detected even in patients without clinical manifestations of autonomic failure [13]. Amyloid deposits in the transverse carpal ligament can cause compression of the median nerve and manifest clinically as carpal tunnel syndrome with pain and tingling in the hands [14].

Patients living in non-endemic areas often develop symptoms later than age 50 years, and may have obscure family history, with less autonomic dysfunction . Neuropathy may involve both large and small fibers concurrently [15]. Although rare, amyloid can also deposit in muscle and cause myopathy, presenting with proximal or distal weakness. Most patients with amyloid myopathy have AL amyloidosis although amyloid myopathy has also been reported in hATTR amyloidosis. Given the rarity of this disease, it has previously been misdiagnosed as limb girdle muscular dystrophy or polymyositis [8].

The diagnosis should be considered in patients with neuropathy and a concurrent family history. In these patients, tissue diagnosis is not necessary and patients can be diagnosed by genetic testing. In patients without a known family history, the diagnosis should be considered in the presence of a progressive, length-dependent, mixed large and small fiber polyneuropathy, especially when associated with carpal tunnel syndrome, autonomic dysfunction, or other multi-systemic involvement. The most common NCS/EMG finding is a length-dependent axonal polyneuropathy. NCS/EMG may also show carpal tunnel syndrome. Conduction slowing is rare [16]. Biopsy of the affected organ, including nerve if neuropathy is present, can demonstrate the presence of amyloid deposits. Other organs that are commonly sampled include abdominal fat, salivary gland, heart, kidney, and muscle. Because of the patchy nature of amyloid deposition , a negative biopsy does not rule out amyloidosis.

In peripheral nerves, amyloid can deposit in the epi, peri or endoneurium in a patchy distribution [17]. Histologically, amyloid is an eosinophilic mass of protein fibrils that stains positive for Congo red and demonstrates yellow-green birefringence under polarized light. Teased fiber studies demonstrate various stages of axonal degeneration with nodules of amyloid indenting myelinating fibers, producing sacculations of the fiber on both sides of the point of compression [17]. When amyloid deposits in the muscle, it can be detected in the interstitium by Congo red stain viewed under polarized light or using fluorescent optics, and can also be found in intramuscular blood vessels. The transthyretin immunostain is highly sensitive and specific for transthyretin derived amyloid [18]; it thus can provide a quick diagnosis for transthyretin amyloidosis in muscle and nerve biopsies. It should be noted that besides hereditary forms, ATTR can also accumulate from wild type transthyretin protein [19], typically in patients older than 80 years. This is referred to as senile systemic amyloidosis. Wild type ATTR deposits are often weak or even negative on Congo red stain [20], but positive for transthyretin immunostain. Genetic testing is necessary to confirm hATTR, particularly in elderly patients. Electron microscopy can usually confirm the presence of amyloid fibrils but has limited utility in determining the subtype of amyloid.

Amyloidosis is a devastating disease. The mean survival is less than 10 years from the diagnosis with death typically secondary to cardiac failure, infection or malnutrition [21]. Historically, liver transplantation has been the standard of care in the treatment of hATTR amyloidosis [22]. However, new therapies have recently been approved by the United States Food and Drug Administration (FDA) for the treatment of neuropathy. These include TTR stabilizers which stabilize the TTR tetramer and suppress the TTR synthesis, and TTR silencers that inhibit hepatic production of TTR. Diflunisal, a TTR stabilizer, is a non-steroidal anti-inflammatory drug that binds to tetrameric TTR and stabilizes it, decreasing fibril formation [23]. Its use is limited largely by gastrointestinal side effects , and it is contraindicated in patients with severe congestive heart failure or renal insufficiency. Tafamidis, a thyroxine-like small ligand inhibitor, similarly stabilizes mutant tetramers. In a randomized double-blind study of patients with V30M mutation given Tafamidis or placebo, the primary outcomes in the quality of life metrics and neuropathy impairment score in the lower limbs were unfortunately not met, although the secondary end points demonstrating less neurologic deterioration were met. It is currently marketed in Europe, Japan and South America but has not been approved by US FDA [24].

TTR silencers include anti-sense oligonucleotides (ASO) and small interfering RNAs (siRNAs) which inhibit mutant and non-mutant TTR production in the liver. The ASO , Inotersen, is a string of nucleotides that prevents TTR protein expression by binding its messenger RNA and thus preventing its translation. In the NEURO-TTR study, both primary endpoints were met with significant benefit inhibiting, slowing or even improving sensorimotor polyneuropathy [25]. Patisiran is an siRNA , which is a double stranded RNA that targets a sequence of mRNA in all TTR variants, inhibiting TTR synthesis in the liver. Patisiran has been demonstrated to halt or reverse the progression of neurologic and cardiac manifestations of hATTR amyloidosis [26].

In summary, amyloidosis should be included early on in the work up of polyneuropathy, particularly with concurrent carpal tunnel syndrome, autonomic dysfunction, or other organ involvement, whether or not the patient has a family history of neuropathy or amyloidosis. With the advent of new therapies , hATTR amyloidosis has become one of the few hereditary causes of polyneuropathy that can be treated.

Pearls